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Review

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

by
María Ovejero-Sánchez
1,2,3,
Rogelio González-Sarmiento
1,2,3,* and
Ana Belén Herrero
1,2,3,*
1
Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
2
Molecular Medicine Unit, Department of Medicine, University of Salamanca, 37007 Salamanca, Spain
3
Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-Spanish National Research Council, 37007 Salamanca, Spain
*
Authors to whom correspondence should be addressed.
Cancers 2023, 15(2), 448; https://doi.org/10.3390/cancers15020448
Submission received: 14 December 2022 / Revised: 3 January 2023 / Accepted: 4 January 2023 / Published: 10 January 2023
(This article belongs to the Special Issue Innovations in Diagnosis, Prognostic Evaluation, and Therapeutic Management of Gynecologic Tumors)
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Abstract

:

Simple Summary

The DNA damage response (DDR) is frequently altered in ovarian cancer (OC), which can be exploited for therapeutic purposes. Moreover, targeting DDR signaling pathways has become an attractive strategy for increasing the effect of DNA-damaging drugs and overcoming chemoresistance. Here, we review the main DDR pathways and their alterations in OC. We also recapitulate the preclinical and clinical studies that target the DDR for the treatment of the disease.

Abstract

The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease.

Graphical Abstract

1. Introduction

Ovarian cancer (OC) includes diverse tumors that affect the ovaries, the fallopian tubes, or the peritoneal cavity. Most (90%) present with an epithelial origin and have been classically divided into five histological subtypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), endometrioid carcinoma, clear cell (CC) carcinoma, and mucinous carcinoma [1,2,3,4,5]. Each subtype exhibits distinct genetic alterations and clinical and prognostic characteristics, which are summarized in Table 1.
OC represents the nineth most common type of cancer, the eighth leading cause of cancer death in women, and the most lethal gynecologic malignancy [6,7,8]. This high mortality is mainly due to asymptomatic tumor growth, which results in a late diagnosis [9]. Moreover, disease relapse is quite common after surgery and standard platinum/taxane-based chemotherapy [10,11], and after further treatments with different chemotherapeutic agents [12]. Therefore, there is a clear need to develop new therapeutic strategies that should ideally target patient-specific genome alterations, the so-called precision medicine. One of these strategies could be novel therapies targeting the DNA damage response (DDR), which is affected in many ovarian tumors.

2. The DNA Damage Response (DDR)

Mammalian genomes are constantly being assaulted by endogenous and exogenous DNA-damaging agents. To fight this threat, cells have evolved the DDR, a collection of interdependent signaling pathways that detect the lesions, signal its presence, and mediate its repair [13]. Defects in these mechanisms cause human diseases, such as cancer; however, defective cells generally display higher sensitivity towards DNA-damaging drugs, which may convert such deficiencies into their Achilles’ heel [14,15].
The most prominent sources of endogenous damage are reactive oxygen species (ROS), which are mostly formed as a byproduct of mitochondrial respiration [16,17]. Another physiological process, DNA replication, may introduce some DNA mismatches that need to be repaired [18]. Additional endogenous sources of DNA lesions are byproducts of lipid peroxidation, endogenous alkylating agents, and reactive carbonyl species, as well as spontaneous hydrolysis of DNA, which results in apurinic/apyrimidinic abasic sites [19,20,21]. On the other hand, the most important sources of exogenous DNA damage include ultraviolet (UV) light, ionizing radiation (IR), chemotherapeutic agents, and other environmental carcinogens that could be inhaled or ingested [22,23] (Figure 1).
These different DNA-damaging agents create a diversity of DNA lesions that activate the DDR. The full system comprises three sets of proteins, namely the sensors of DNA damage, the transducers, and the effectors (Figure 1). The sensor proteins actively search the genome for the presence of DNA damage. If damage exists, they transmit a signal to other proteins called transducers, such as ATM and ATR kinases. These transducers recruit and activate effector proteins, such as CHK1, CHK2, and p53, that activate cell cycle checkpoints allowing DNA repair or triggering apoptosis or senescence. The goal is to avoid the transmission of erroneous genetic information to daughter cells [13].
The type of DNA lesion determines the repair mechanism employed by the cells (Figure 2). DNA alkylation produced by endogenous metabolites or alkylating drugs is repaired by the direct reversal mechanism (DR) [24]; replication errors are corrected by the mismatch repair (MMR) pathway [25]; bulky adducts caused by a variety of DNA-damaging agents, including pyrimidine dimers produced by UV exposure, are repaired by nucleotide excision repair (NER) [26]; single-strand breaks (SSBs) and small base damage caused by endogenous or exogenous sources can be repaired by base excision repair (BER) [26]; Finally, double-strand breaks (DSBs) produced by IR, ROS, or some chemotherapeutics are solved by homologous recombination (HR) or nonhomologous end joining (NHEJ) repair pathways [27].
These core DNA repair pathways may be interconnected and, under certain circumstances, failure to repair by one of the pathways can be compensated by the activity of others. Moreover, all these repair pathways do not function in isolation, but they are integrated with complementary processes that are essential to overall genome maintenance. These processes, which also form part of the DDR, as mentioned before, include cell cycle checkpoints, the p53 pathway, and chromatin remodeling factors that facilitate the accessibility of repair proteins.
The following sections describe the main DDR pathways, the proteins involved, and their alterations in OCs, which is summarized in Table 2 and Table 3. The potential of targeting these pathways in OC treatment is also overviewed and summarized in Table 4 (preclinical studies) and Table 5 (clinical studies). The information shown in the tables was found using Google Scholar (https://scholar.google.es accessed on 31 October 2022) or PubMed (https://pubmed.ncbi.nlm.nih.gov accessed on 31 October 2022) databases. Search terms included: “DNA damage response”, “DNA repair”, or the names of the different DDR pathways and compounds together with the term “ovarian cancer”. ClinicalTrials database (https://beta.clinicaltrials.gov accessed on 30 November 2022) was also employed to obtain information concerning clinical studies. The name of each compound and “ovarian cancer” were used as search terms. Scientific literature derived from each clinical trial was also searched using Google Scholar or PubMed.

3. DNA Repair Pathways and Their Alteration in OC: Implications for Therapy

Alterations of DNA repair pathways, caused by genetic inactivation and/or epigenetic mechanisms, represent a common feature of carcinogenesis; they drive malignant transformation by the accumulation of genomic alterations in the cells [219]. Defects in DNA repair can occur at the germline, conferring an increased risk of developing cancer, or can be somatic, which might also result in sporadic cancers or affect sensitivity to therapy.

3.1. Direct Reversal Repair (DR)

During normal metabolism, or as a result of exposure to various carcinogens or alkylating agents, the nitrogenous base guanine can become methylated. The enzyme methylguanine DNA methyltransferase (MGMT) deals with this damage by transferring the methyl group at the 6-position of guanine to a cysteine group located in the MGMT active center. Then, the enzyme is irrevocably inactivated, which is the reason why MGMT is known by the term ‘suicide protein’ [28]. This repair system is called direct repair because it acts without the need to excise the DNA helix (Figure 2).
Loss of MGMT expression has been described in many tumor types, including glioblastoma, lymphoma, breast and prostate cancer, and retinoblastomas, and its usually due to promoter methylation [220]. Interestingly, defects in direct repair by MGMT have been linked to the therapeutic success of alkylating agents, especially temozolomide (TMZ). Thus, in glioblastomas, where approximately 45% bear a methylated MGMT promoter, treatment with TMZ produces a survival advantage for these types of patients [221] and is used as an oral alkylating agent to treat the disease.
In ovarian cancer, Roh et al. [51] detected MGMT promoter hypermethylation in 14% of the samples analyzed (86 epithelial OCs). In addition, a meta-analysis including 10 studies and 910 OC samples concluded that MGMT-inactivation might be associated with carcinogenesis in certain histological types (non-serous carcinomas) [52] (Table 3). Additionally, a role for MGMT in the chemoresistance of ovarian cancer has been recently described by Wu et al. [222]. The authors found that the deubiquitinating enzyme 3 (DUB3) stabilized the anti-apoptotic protein MCL1 and that MGMT was a key activator of DUB3 transcription. Consequently, the MGMT inhibitor PaTrin-2 effectively suppressed OC cells with elevated MGMT-DUB3-MCL1 expression. This inhibitor, known as Lomeguatrib, has also proven to sensitize cells from advanced solid tumors to temozolomide [97] (Table 4) and was tested in clinical trials to determine the optimal doses in patients with several tumors, including OC [171] (Table 5).

3.2. Mismatch Repair (MMR)

The DNA mismatch repair system corrects spontaneous base–base mispairs and small insertions–deletion loops (indels) generated by failures in DNA replication. It is therefore one of the most important guardians of genome integrity. Defects in MMR increase the mutational rate of the cell and alter the sequence lengths within microsatellites, which is called microsatellite instability (MSI) [18]. The first step in this repair pathway is the recognition of the lesion. The most abundant mismatch-binding factor is composed of the ATPases MSH2 and MSH6, which recognizes single base substitutions or small insertion or deletion loops (IDLs) [29,30,31] (Figure 2). The repair of larger IDLs is initiated by the MSH2–MSH3 complex. Upon damage recognition, these complexes bind to the mispairing site and recruit another complex formed by MLH1 and PMS1 or PMS2. This complex has endonuclease activity and, in the presence of ATP, excises the DNA chain at the error site. The stabilizing protein RPA allows the binding of proliferating cell nuclear antigen (PCNA) and replication factor C (RFC) to protect the gap generated in the DNA. Subsequently, DNA exonuclease I (Exo1) enters into the DNA structure guided by the two complexes (MSH2–MSH3/MSH6 and MLH1–PMS1/PMS2) and removes the damaged area along with other nearby nucleotides. At this point, the DNA polymerase (Pol δ) synthesizes DNA in the deleted region, thus, errors that escaped polymerase proofreading in the first place will finally be resynthesized again by Pol δ as part of mismatch repair [32]. Finally, PCNA factor checks the synthesis of nucleotides, and DNA ligase I seals the nick [33].
Defects in the MMR are associated with Lynch syndrome, an autosomal dominant syndrome that mainly predisposes to colon cancer, but also to endometrial and ovarian cancer [60,223]. In Lynch syndrome, most mutations occur in MLH1 (42%) and MSH2 (33%), followed by MSH6 (18%) and PMS2 (7.5%) [53]. Patients with this hereditary condition usually acquired only one mutated allele from one of the progenitors and lose the second allele somatically via mutation or methylation. Lynch syndrome confers a 10–15% risk of developing low-grade or clear cell OC, which tends to develop at an early age [54,55]. HGSC seems little influenced by defects in MMR, as revealed by a large study of 2222 ovarian cancer cases that found defective MMR in only 17 cases [224].
In sporadic cancers, alterations in the MMR pathway have also been described. The most common finding is promoter hypermethylation of the MLH1 gene, which leads to its silencing, and has been observed in sporadic MSI-cancers including colorectal, endometrial, and ovarian cancer [56]. The frequencies of MLH1 promoter hypermethylation ranged between 10% and 50%, with the higher estimates reported in MSI-tumors [57,58].
It is known that MMR-deficient cells are resistant or acquire resistance to common chemotherapeutic drugs, such as 5-FU, used against colorectal cancer, or cisplatin and carboplatin, widely used for the treatment of ovarian cancers [225,226]. This fact, together with the significant frequency of MMR-deficient tumors, highlighted the need to identify new therapeutic strategies that target vulnerabilities exhibited by these malignant cells. Synthetic lethal approaches have been explored with the aim of killing MMR-deficient cells and several candidates have been identified in preclinical studies [225]. However, none of them have yet been explored in clinical studies with OC patients. Therefore, although various laboratory methods exist to identify MMR-deficient ovarian cancers, such as microsatellite instability analysis, immunohistochemistry, promoter hypermethylation testing, and germline mutation analysis, strategies to specifically target those tumors are not yet available. It has been reported, however, that defects in MMR create a ‘mutator phenotype’ that results in the synthesis of “non-self” immunogenic antigens, which increase the susceptibility to immune checkpoint inhibition [227]. That seems to be the explanation for the good response of different MMR-deficient tumors to single-agent PD-L1. Indeed, the US Food and Drug Administration (FDA) has approved pembrolizumab, one immune checkpoint inhibitor, for any MMR-deficient relapsed solid tumor. This indication is not yet available in Europe but might orient trials with relapsed endometrioid or clear cell OCs and MMR deficiency [228].

3.3. Nucleotide Excision Repair (NER)

NER eliminates various bulky (helix-distorting) lesions, such as those produced by ultraviolet light (UV), certain environmental chemical mutagens, or the inter- and intra-strand crosslinks induced by chemotherapeutic agents like cisplatin [34,229] (Figure 2).
Two NER sub-pathways have been described: transcription-coupled NER (TC-NER) and global genome NER (GG-NER). They differ in the damage-detection mechanisms but utilize the same machinery to excise and repair the damage [34]. TC-NER repairs the lesions present in the transcribed strand of active genes. It is initiated by the RNA polymerase stalled at the lesion together with TC-NER-specific factors CSA, CSB, and XAB2. GG-NER repairs the lesions that occur anywhere in the genome and is initiated by the GG-NER-specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein) [26].
Once the damage has been detected, the XPA/RPA and TFIIH complexes are recruited and remain bound to the DNA. The TFIIH complex, formed by different helicases such as XPB and XPD, is responsible for opening and stabilizing the DNA helix. Next, two endonucleases (XPG and XPF/ERCC1) cleave on both sides of the lesion, eliminating several nucleotides. After excision, the resulting gap of approximately 30 nucleotides is filled in by DNA synthesis and ligation. This process is carried out by the action of replication factors (PCNA and RFC); DNA polymerases δ, ε, and κ; and DNA ligases I and III [34,35].
Defective NER is characteristic of the skin cancer-prone inherited disorder xeroderma pigmentosum, which is characterized by extreme UV sensitivity, but might also occur in other sporadic cancers [230]. Thus, gene polymorphisms in some NER proteins have been associated with lung, skin, and bladder cancers [60,230].
In ovarian cancer, one study detected an association between some SNPs in NER proteins and ovarian cancer susceptibility [59]. However, the most significative connection between NER and OC came from the TCGA data set, which revealed that 8% of HGSC OCs harbored alterations in some NER genes, which included homozygous deletions, missense, or splice site mutations [60,61].
As mentioned previously, the NER signaling pathway is involved in the repair of platinum-induced adducts; therefore, NER deficiency may increase sensitivity to cisplatin, whereas NER upregulation might mediate cisplatin chemoresistance. In this regard, Ceccaldi et al. showed that patients with HGSC tumors bearing NER gene mutations displayed improved survival to platinum compared to those that did not bear NER alterations [61]. Moreover, two NER mutations (ERCC6-Q524 and ERCC4-A583T), which have been identified in the two most sensitive tumors, were functionally associated with platinum sensitivity in vitro. On the other hand, it has been recently described that the tyrosine kinase receptor TIE-1 mediates OC platinum resistance by promoting NER [231].
Based on all these data, the development of NER inhibitors could represent a therapeutic strategy against NER-deficient or platinum-resistant OCs. Currently, there are no targeted therapies approved by the FDA specifically for patients with germline or somatic mutations in NER pathways genes. However, several small inhibitors have been developed during the last years with a variable potency [60,232,233]. Certain NER inhibitors, such as MCI13E, TDRL-505, or TDRL-551, have shown antitumor activity in OC cells [98], and TDRL-551, an inhibitor of RPA protein, produces a synergistic cytotoxic effect when combined with platinum or etoposide in OC cells [98] (Table 4).
Another promising group of compounds with anti-tumor activity is the ecteinascidin family, which includes trabectedin and lurbinectedin [99]. These compounds interfere with the NER machinery, attenuating the repair of certain NER substrates, and use NER proteins to exert their cytotoxic effect [100,234]. Preclinical studies have shown that lurbinectedin and trabectedin were effective in the treatment of cisplatin-sensitive and cisplatin-resistant OC cells and xenograft tumor models, especially when they were combined with cisplatin [99,100,101,102]. In addition, Casado et al. have suggested that trabectedin could re-sensitize tumor cells to platinum therapy [235]. The combination of lurbinectedin/trabectedin with other antineoplastic drugs, such as doxorubicin or irinotecan, also exerted a synergistic effect in OC cells [236,237]. Its combination with pegylated liposomal doxorubicin (PLD) improved progression-free survival and overall survival over PLD alone in patients with recurrent OC [238,239,240]. Indeed, trabectedin together with PLD is indicated for the treatment of patients with relapsed platinum-sensitive OC [241]. Based on these preclinical studies, several clinical trials have recently explored the effectivity of trabectedin and lurbinectedin in monotherapy and in combination with PLD or other drugs [172,173,174,175,176,177,178,179,180,181,182,189,190,191,192,193] (Table 5).

3.4. Base Excision Repair (BER)

BER corrects small base lesions (alkylations, oxidations, deaminations, depurinations) or single-strand breaks (SSBs) resulting from endogenous or exogenous sources, such as radiation or chemotherapeutic agents [36]. This repair pathway is initiated by a DNA glycosylase that recognizes and removes the damaged base, leaving an abasic site that is further processed in several steps: incision (which creates a SSB), end processing, DNA synthesis, and ligation. There are 11 families of glycosylases responsible for detecting the different types of lesions, for example, OGG1, UNG, or MUTYH. Several polymorphisms in these glycosylases have been linked with various cancers, such as colorectal, oesophageal, gastric, or lung cancer [62,242]. In the case of colorectal cancer, it has been described a predisposition syndrome that is associated with biallelic-inherited mutations of MUTYH [243].
The main endonuclease responsible for the incision step is APE1 that generates a SSB in the DNA. SSBs formed by the action of this enzyme, or those directly created by endogenous or exogenous sources, are rapidly detected and bound by PARP1. This protein stabilizes the DNA ends and adds a poly-ADP-ribose chain that recruits downstream proteins such as XRCC1. XRCC1 serves as a scaffold that attracts other proteins required for the repair, specifically, DNA ligase III (LIG3), DNA polymerase β, and bifunctional polynucleotide kinase 3′-phosphatase (PNKP) [37,38] (Figure 2).
The implication of BER defects in the development of OC is not clear. However, some studies that have reported a connection, such as those that associate several polymorphisms in the glycosylase OGG1, the endonuclease APE1, or the XRCC1 protein with an increased risk of OC [62,63,64,65,66,67,68]. High nuclear expression of the endonuclease APE1 has also been associated with the development of HGSC, and a correlation with worse overall survival and greater resistance to platinum therapy was reported [69]. In another study, APE1 overexpression was described to promote OC progression. Indeed, the authors found that APE1 downregulation inhibited ovarian cancer cell proliferation, which pointed out this protein as a potential therapeutic target [244]. Moreover, APE1-knockdown cells showed a stronger apoptosis induction after being exposed to DNA-damaging agents, such as UV, camptothecin, or cisplatin [244,245]. Therefore, the use of DNA damage agents together with an APE1 inhibitor could represent a therapeutic strategy. Several APE1 inhibitors have been developed, such as methoxyamine or E3330 (Table 4). Methoxyamine (TRC102) has been described to enhance temozolomide cytotoxicity in several OC cell lines by increasing the amount of DNA damage and apoptosis [103]. This combined treatment was tested in clinical trials for several solid tumors, including granulosa cell OC [195] (Table 5). The E3330 inhibitor and several analogs have shown to inhibit OC cell proliferation [104,105]. Spiclomazine and fiduxosin, two inhibitors of APE1/NPM1 interaction, have also been described to decrease proliferation and sensitize OC cancer cells to bleomycin [106].
The most important BER inhibitors used in the clinic are those that target PARP1. PARP inhibitors (PARPi) were first approved for the treatment of breast and ovarian cancers with defects in the HR pathway due to BRCA1 or BRCA2 mutations. The synthetic lethality between PARP inhibition and BRCA inactivation was first reported in 2005, where it was proposed that inhibition of PARP1 activity would lead to replication fork collapse and the subsequent formation of DSBs, lesions that require the HR pathway to be repaired [107,108]. New studies have shown that, in addition to women with BRCA-mutated tumors, initial treatment with PARP inhibitors also benefits other OCs with defects in HR, which is a major step forward.
There are three PARP inhibitors approved for use in OC [246,247]: olaparib, rucaparib, and niraparib. Olaparib was the first PARPi approved for clinical use. It currently has two indications in patients with advanced OC. The first is for treatment in patients with a mutation or suspected germline mutation in BRCA1/2 after three or more prior lines of chemotherapy. The second is as maintenance treatment in patients with recurrent OC who are in partial or complete response to platinum-based chemotherapy [246,247]. Rucaparib was the second PARPi approved for OC treatment and presents two indications in OC: maintenance treatment in patients with recurrent OC who are in complete or partial response to platinum-based chemotherapy, and the treatment of patients with pathogenic BRCA mutations (germline or somatic) associated with this tumor, who have undergone two or more lines of chemotherapy [246,247]. Finally, niraparib is indicated for the maintenance treatment of patients with recurrent OC who have a partial or complete response to platinum-based chemotherapy [246,247].
The clinical trials exploring the PARPi olaparib, rubaparib, niraparib, talazoparib, and pamiparib in monotherapy or in combination with other drugs are shown in Table 4 and Supplementary Table S1. Many of them are DDR-interfering drugs, such as DNA-damaging agents (temozolomide, carboplatin, cisplatin, or pegylated liposomal doxorubicin) or inhibitors of DNA damage response (ATR inhibitors, WEE1 inhibitors, or BET inhibitors). These combinations are supported by recent evidence that suggests that PARP1 may also have a role in other DNA repair pathways, including NER, MMR, and DSB repair, the pathway described in the next section [248,249,250].
Several studies have described that those tumors bearing mutations in BER genes had increased neo-antigen production and PD-L1 expression [251]. Therefore, the combination of PARPi with immune checkpoints inhibitors such as pembrolizumab, dostarlimab, durvalumab, tremelimumab, atezolizumab, or avelumab, has also been studied. Moreover, PARP inhibitors have been combined with angiogenesis inhibitors such as bevacizumab, everolimus, or surufatinib. These combinations have been tested because angiogenesis and PARP inhibitors are indicated as front-line or as maintenance treatment for OC patients.

3.5. DNA Double-Strand Break Repair by Homologous Recombination (HR)

DSBs are formed following exposure to ionizing radiation or some chemotherapies, and by the action of free radicals produced by endogenous metabolism [252]. This type of lesion represents a major threat to genome stability since it can lead to profound genome rearrangements [253]. Consequently, inherited, or somatic defects in DSB repair increase cancer susceptibility. Specifically, inherited defects predispose patients to cancer, especially OC and breast cancer. DSBs are repaired by two main pathways in mammalian cells: the efficient, but error-prone, nonhomologous end-joining (NHEJ) or the less efficient, but error-free, homologous recombination (HR). In case of defective NHEJ or HR, alternative (Alt)-NHEJ provides a backup mechanism where PARP1 is also involved [248].
The HR pathway is high-fidelity because it uses the homologous sister chromatid as a template to repair the lesion, and consequently, it is restricted to S and G2 phases of the cell cycle, when DNA has been replicated. The first step of the pathway is to process the ends of the DSB by nucleolytic resection. This is carried out by the MRN complex, consisting of MRE11, RAD50, and NSB1 [39,40]. The complex binds to both sides of the DSB and activates the kinase ATM, which controls cell cycle checkpoints, arresting the cell cycle, and recruiting a larger number of DNA repair proteins, including BRCA1. This protein promotes end resection and participates in HR repair at multiple stages [41]. The DNA end-resection mechanisms lead to the formation of 3′-tailed ssDNA. ATR kinase can be activated by these ssDNA intermediates controlling, therefore, the later steps of HR. The ssDNA ends are then coated by RPA, a protein that protects them from the action of nucleases. BRCA1 also forms complexes with other proteins such as the PALB2, which in turn binds to BRCA2 and enables RAD51 filament formation that replaces RPA [42]. RAD51 is a recombinase; it facilitates the invasion of the sister chromatid allowing the formation of a D-loop structure that leads to repair. Finally, the DNA polymerase and the DNA ligase definitively repair the damage [39,40]. Together with the mentioned proteins, many others have also been involved in the global HR process [40].
It is estimated that approximately 50% of OCs harbor some HR deficiency [73]. Germline mutations in the BRCA1/2 genes are the most frequent and well-known mechanisms and appear in approximately 20% of HGSCs (Table 1). However, germline or somatic mutations in other HR genes and epigenetic modifications have also been implicated in OC [70,71,72]. Starting with the MRN complex, associations between mutations in MRN complex genes and OC susceptibility have been observed [74]. Moreover, an immunohistochemical study revealed that 41% of epithelial low-grade OC lacked the MRN complex and 10.3% of tumors lacked RAD50, specifically [75]. Mutations in RAD51C or RAD51D have also been associated with an increased risk of OC, having potential use in routine clinical genetic testing [76]. Regarding epigenetic modifications, the promoter region of the RAD51 gene has been found hypermethylated in 3% of HGSC patients, leading to a deficiency in HR [60].
Considering that HR deficiency is a major hallmark of OC, considerable efforts are being dedicated to specifically target those defects. As mentioned previously, a synthetic lethal strategy by targeting PARPi in HR-deficient OCs has attracted great attention, in view of its favorable clinical result; however, treatment with PARPi could benefit not only BRCA1/2 carriers, but also other OCs with HR deficiencies. For example, Zhang et al. reported that 18% of BRCA WT OC patients (from a total of 220) exhibited RAD50 deletions, which were also associated with better OS and PFS with PARP inhibitors [77]. In fact, Mukhopadhyay et al. found that all HR defective OCs, identified by a RAD51 immunofluorescence assay, were more sensitive to PARPi in vitro and showed enhanced clinical platinum sensitivity [254].
There are some drugs able to inhibit HR that could also be combined with many other molecules that induce DSBs to increase the cytotoxic effect. Consequently, several works have combined genotoxic agents with DNA repair inhibitors in vivo and have found cytotoxic effects in tumor cells and lower toxicity in normal cells [255,256,257]. In this regard, it has been observed in many clinical cases that BRCA WT patients also respond to DNA damage/repair targeted therapeutic drugs. These results might be explained by the presence of other defects in HR independent of BRCA1/2 mutations, as mentioned before, by other DDR defects, or by the increased proliferation rate that sensitizes tumor cells to DNA damage. In this regard, our group has recently described that the antimalarial drug chloroquine induces DNA DSBs in OC, and its combination with Panobinostat, a histone deacetylase inhibitor (HDACi) that inhibits HR [109], or NHEJ inhibitors, synergistically induce OC cell death [109,116]. Whether these combinations are more effective in HR-deficient cells needs to be further explored. Panobinostat treatment has been tested in clinical trials showing potential anticancer activity against OC [196].
Another HR inhibitor investigated is mirin, which inhibits Mre11 [258]. It has been described that this compound increased sensitivity to DNA-damaging agents such as cisplatin, carboplatin, or chloroquine in OC cells [109,110,111]. Other compounds present in the pomegranate extract have also been reported to downregulate the MRN complex and some genes involved in HR repair [258]. The authors found that the main components of pomegranate (ellagic acid and luteolin) reduced the proliferation and migration of OC cells [115]. In addition, this compound inhibited tumor growth in xenograft models of OC [115] (Table 4).

3.6. DNA Double-Strand Break Repair by Nonhomologous End Joining (NHEJ)

NHEJ is the other pathway that deals with DNA DSBs. This pathway is considered fast and efficient; however, it may cause the loss of some nucleotides on both sides of the break or an alteration of the base pair sequence at the break site [43,44]. In general, this loss or alteration is not critical for the cell, since the genome is rich in repetitive sequences; however, both downregulation and upregulation of the pathway can lead to genome instability [259]. NHEJ repair can take place in all phases of the cell cycle, although it has low activity in the S and G2 phases [43,44]. Two NHEJ sub-pathways have been described, the canonical and the alternative pathway [43].
The canonical NHEJ repair pathway requires the activity of different proteins: Ku70, Ku80, DNA-dependent kinase catalytic subunit (DNA-PKcs), Artemis, DNA ligase IV, XRCC4, and XLF (Figure 2). When the break is detected, the heterodimer Ku70/Ku80 binds to DSBs with high affinity, protecting the DNA from the action of the exonucleases and serving as a scaffold to recruit the other NHEJ factors to the damage site, such as DNA-PKcs. This protein is a member of phosphatidylinositol-3 (PI-3) kinase-like kinase family (PIKK), which also includes two other kinases important in the cellular response to DNA damage, ATM and ATR. If the DNA ends of the break are not compatible, they must be trimmed, a process that is carried out by the nuclease Artemis. Once the ends are compatible, ligation is carried out by a complex consisting of XRCC4, XLF, and DNA ligase IV [43,44] (Figure 2).
The alternative NHEJ repair pathway is less characterized but is considered an important promoter of cancer genome instability [45]. It is independent of the heterodimer Ku70/Ku80 and employs regions of microhomologies, which may be distant from the breakpoint, to repair the lesion. The pathway is therefore associated with the loss of genetic material and is highly mutagenic. Several studies propose the role of Alt-NHEJ as a backup pathway when C-NHEJ or HR are defective [45,46]. The key proteins in this pathway are PARP1, DNA ligase III, and XRCC1, and it is believed that the process is promoted by DNA polymerase Θ. During the repair, PARP1 recognizes the double-strand break and binds to DNA in competition with Ku70/80. XRCC1 and DNA ligase III form a complex that is responsible for binding the double-strand breaks.
In OC, one study carried out by McCormick et al. described that the NHEJ repair pathway was altered in up to 50% of tumors independent of the HR repair. Dysregulation of this pathway can be due to mutations in the genes involved, both in germline and somatic [60], or to their overexpression. For example, elevated expression of DNA-PKs is a common finding in HGSC and correlates with an advanced stage of the disease, as well as with a high grade, worse survival, and reduced platinum sensitivity [78]. Another example is the overexpression of DNA polymerase Θ, which promotes Alt-NHEJ pathway, has been identified in ovarian serous carcinomas [79]. Overexpression of XRCC4 has been linked to poor outcome in OC and has been proposed as a candidate biomarker for OC [80]. On the other hand, single nucleotide polymorphisms (SNPs) in the DNA ligase IV or XRCC1 gene have been found in some OCs. These variants might affect DNA repair or sensitivity to platinum treatments [60].
In recent decades, diverse DNA-PKs inhibitors have been developed. They increase radio- and chemosensitivity and differ in their potency and selectivity [260]. The inhibitors NU-7026 and NU-7441 share a common chemical structure; however, NU-7441 showed a higher potency in inhibiting DNA-PKs. Both compounds have proven their efficacy in enhancing the cytotoxicity of agents that damage DNA, such as irradiation, chloroquine, or cisplatin, in ovarian cancer cell lines [116,117,118]. Peposertib (M3814), an oral DNA-PKs inhibitor, increased radiosensitivity and sensitized tumor cells to different chemotherapeutic drugs [119], such as etoposide [120,256]. Moreover, it also increased cytotoxicity to pegylated liposomal doxorubicin in a xenograft OC model [256]. This combination is being studied in human clinical trials for patients with recurrent HGSC and LGSC ovarian carcinomas [261] (Table 5). Another DNA-PKs inhibitor is AZD7648, which increased cytotoxicity to irradiation and to several chemotherapeutic drugs such as doxorubicin or PARP inhibitors in tumor cell lines including OC cells [121,255]. Moreover, this inhibitor has been proven to sensitize OC patient-derived xenografts to PLD and olaparib and to prevent abdominal metastases [122]. According to these data, the combination of DNA-PK inhibitors and a DNA-damaging agent should be considered for further preclinical and clinical studies due to their therapeutic potential.

4. DDR-Associated Pathways and Their Alteration in OC: Implications for Therapy

As mentioned before, in addition to core DNA repair pathways, other DDR-associated elements exert an essential role in maintaining DNA integrity. These include chromatin remodeling factors, which enable access to DNA damage, the checkpoint signaling, and p53 pathway, which allow time for repair preventing cells from entering mitosis with substantial unrepaired damage.

4.1. Chromatin Remodelers

DNA in eukaryotes is highly compacted with the help of histone proteins forming the chromatin. Therefore, DNA damage repair requires opening of the chromatin structure to facilitate the accessibility of DNA repair proteins. Modification of chromatin occurs via two mechanisms: posttranslational modification of histones or displacement of these proteins, this last requires the action of ATP-dependent chromatin remodeling complexes and histone chaperones. Ubiquitination is an example of histone posttranslational modification important in the DDR. It has been described that this modification changes the chromatin structure in the vicinity of DSBs and serves as a platform to select and recruit repair proteins [262]
The ATP-dependent mechanisms use the energy of ATP hydrolysis to disrupt the DNA–histone contacts and constitute most of the remodeling activity in the cell [47]. Four families of multi-subunit chromatin remodeling complexes have been described: SWI/SNF, INO80, CHD, and ISWI. They differ in their epigenetic reader domains, which recognize the specifically modified histone tails.
It is becoming increasingly clear that ATP-dependent chromatin remodeling complexes play important roles in the establishment and progression of human cancers, which is due, at least in part, to their role in the DDR. Somatic mutations and deregulated expression of several subunits of chromatin remodeling complexes have been described in many cancer subtypes [263], being subunits of the SWI/SNF family the most frequently altered. For example, mutations in INI1 and ARID1A components, both involved in the DDR [264], are frequently observed in several tumors from diverse tissues including the stomach, large intestine, central nervous system, bone, endometrium, liver, urinary tract, and ovary [263]. Interestingly, around 30% of endometrioid OCs display mutations in ARID1A [81,82], which has also been found mutated in 50% of CC carcinomas [81,82,83,84]. ARID1A is considered a tumor suppressor through multiple mechanisms that include transcriptional regulation, cell cycle control, replication stress, and DNA repair. ARID1A has been described to play a role in DSB repair by helping the recruitment of the ATPase subunit of the SWI/SNF complex to DNA damage sites [265]. In addition, it also helps to recruit the NHEJ factors Ku70/Ku80 to the DSB sites and maintains checkpoint signaling through its interaction with ATR [265]. Moreover, a putative role of ARID1A in MMR has also been described. In summary, ARID1A protects the genome by interacting with the proteins of different DNA repair mechanisms. Its inactivation in an important number of OCs makes it a good candidate for synthetic lethal targeting [265].
The chromatin remodeling complex INO80 is also recruited to DSBs and is needed for efficient repair by HR and probably by NER [266]. Mutations in INO80 subunits are not abundant in human cancers; however, several INO80 subunits have been found overexpressed. In the case of OC, amplification of the ACT6LA subunit have been detected, which correlates with platinum chemoresistance [88,90].
Regarding CHD chromatin remodeling complexes, mutations in CHD5 and overexpression of CHD8 subunits have been reported in OCs [88]. CHD4, which forms the nucleosome remodeling and deacetylase (NuRD) complex, is overexpressed or mutated in some OCs [85]. Thus, Zhao et al. [86] identified 11 out of 52 patients that exhibited a heterozygous somatic CHD4 mutation, and Le Gallo et al. [87] also reported a somatic mutation in CHD4 in 17% of patients with serous endometrial cancer. In addition, it has been described that BRCA2-mutant ovarian cancers with reduced CHD4 expression significantly correlate with shorter progression-free survival and shorter overall survival [267]. On the other hand, CHD4 overexpression was also reported to correlate with poor survival and was significantly higher in platinum-resistant HGSC [89].
Finally, ISWI family members also display genetic status abnormalities in human cancers, including OCs [268]. Interestingly, deregulated expression is closely linked to drug response and patient outcome.

4.2. Checkpoint Factors

DNA damage and replication stress initiate the DDR through the activity of two signaling kinase proteins: ATM and ATR, both belonging to the phosphatidylinositol-3 (PI-3) kinase-like kinase family (PIKK). ATM is generally activated by a DSB, whereas ATR is activated by a SSB, DNA replication stress, and DNA-end resection, which occurs during DSB repair, as mentioned before [48]. Upon their recruitment to DNA damage sites, both kinases activate the DNA damage checkpoints, which arrest the cell cycle allowing time for repair. The response is performed through the phosphorylation and activation of the Checkpoint Kinase 2 (CHK2), by ATM, and Checkpoint kinase 1 (CHK1), by ATR, although an extensive communication exists between the two signaling pathways.
One of the main substrates of CHK2 is p53, whose activation by phosphorylation promotes the upregulating of p21, an inhibitor of cyclin-dependent kinases that induce a G1/S transition arrest [48,49]. Activation of CHK2 also phosphorylates CDC25C leading to its degradation, which prevents the activation of downstream signaling pathways such as p21 and cell cycle B1 and result in a G2/M arrest [49].
CHK1, activated by ATR, inhibits S phase DNA replication and G2/M phase transition through the phosphorylation and activation of WEE1 and CDC25C [50]. The kinase WEE1 regulates the entry into mitosis by negatively controlling the cyclin-dependent kinases CDK1 and CDK2.
Germinal mutations in ATM produce Ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder with an increased risk of developing cancer (40%), particularly leukemias and lymphomas [269]. Somatic ATM mutations also occur in several sporadic tumor types, especially in hematologic malignancies [91]. The risk of OC has been found to be slightly elevated for people with an inherited ATM mutation (a lifetime risk of about 2–3% versus 1.3% for the general population) [92], and the percentage of OC tumors with ATM somatic mutations seems to depend on the OC subtype. A recent study analyzing 207 ovarian cancer samples from a Japanese population reported that ATM mutations are more frequent in CCC (9%) and EC patients (18%) than in HGSC patients (4%) [270].
Mutations in ATR are much rarer that in ATM. They are not associated with hereditary breast and ovarian cancer (HBOC) syndrome, only with Seckel syndrome, an autosomal recessive disorder not implicated in malignancy [271].
Regarding CHK2, genetic testing for various hereditary cancer predispositions has identified mutations in this gene among the most frequent germline alterations. However, despite many published results, the association of CHK2 mutations with OC can be neither confirmed nor rejected, due to the presence of many variants of unknown significance (VUS) that affect clinical interpretation [272]. On the other hand, somatic mutations of CHK2 have been reported in small subsets of diverse types of sporadic cancers including OC [93]. On the contrary, and despite playing a central function in the DDR, no germline, or somatic mutations in CHK1 have been conclusively associated with human disease [273], which is probably due to its essential role in cell proliferation and survival.

4.2.1. ATM Inhibitors

ATM is considered a tumor suppressor. ATM mutations are predicted to result in enhanced sensitivity to platinum chemotherapy [91]. However, when ATM is present in tumor cells, it confers resistance to ionizing radiation and DNA-damaging agents. For this reason, ATM inhibitors have been developed for use in cancer therapy and have been reported less harmful for non-tumoral cells [274].
Multiple preclinical studies have analyzed the efficacy of ATM inhibitors in monotherapy or in combination with other chemotherapeutic drugs in several tumors, including OCs (Table 4). In general, these inhibitors decreased OC cell proliferation and synergized with other compounds, such as fenofibrate, an inhibitor of PPARA, 673A, or DNA-damaging agents, including ionizing radiation, trabectedin, and lurbinectedin [123,124,125,126,275].

4.2.2. ATR Inhibitors

Like ATM, ATR inhibition decreases both DNA checkpoint response and DSB repair, enhancing the efficacy of IR and DNA-damaging drugs. Moreover, it is known that p53- or ATM-defective cells can only rely on ATR to avoid a mitotic catastrophe for excessive DNA damage accumulation after these treatments. Based on this knowledge, many ATR inhibitors (ATRi) are under preclinical and clinical investigation as monotherapies or in combination with other anticancer agents such as cisplatin, topotecan, gemcitabine, trabectedin, or PARPi [125,127,128,276,277,278,279]. Preclinical results have shown inhibition of cell proliferation [127,129,136,137,139] and, in many cases, synergistic effects in combination with different drugs [124,125,128,130,131,132,133,134,135,138,140,141,142,145,279], which are summarized in Table 4. Clinical results have shown that ATR inhibitors (celarasertib, berzosertib, elimusertib, and gartisertib) were safe and well tolerated and presented preliminary antitumor activity in OC patients [201,280]. In addition, it has also been studied its combination with other chemotherapeutic drugs such as PARP inhibitors [198,199], carboplatin [200], cisplatin [199,201,202], topotecan [200,203], or gemcitabine [204,281]. Clinical results of ATR inhibitors are summarized in Table 5.

4.2.3. CHK1 and CHK2 Inhibition

Several CHK1and CHK2 inhibitors with different potency and selectivity have been developed. Numerous CHK1 inhibitors have been studied in preclinical studies such as SRA737, V158411, LY2880070, MK-8776, or PF-477736. These inhibitors caused inhibition of cell proliferation of OC cells and enhanced sensitivity to DNA-damaging agents [128,133,144,146]. The inhibitor SRA737 was reported to synergistically enhance the cytotoxicity of PARPi (niraparib, olaparib) in OC cells [143]. Moreover, treatment with SRA737 in HGSC patients-derived xenograft models, where PARPi showed limited activity, resulted in a significant stabilization of the disease [282]. A phase I/II trial has tested the security and efficacy of SRA737 in monotherapy or in combination with gemcitabine and cisplatin in several cancer patients, including HGSC OC patients [205,206]. It was reported that low doses of gemcitabine could increase their activity by induction of replication stress [206]. Moreover, LY2880070 has also been tested in clinical trials together with low doses of gemcitabine and has proven to be well-tolerated in OC patients [207].
Regarding CHK2 inhibitors, PV1019, PHI-101, C342, and AZD7762 have shown to inhibit OC cell proliferation and synergistically increased the cytotoxic effect of DNA-damaging agents [147,148,149,150,151]. PHI-101, which elicits a synergistic lethal response in combination with olaparib regardless of BRCA and TP53 status, potentiated the toxicity triggered by genotoxic agents such as cisplatin and topotecan. Recently, a phase I clinical trial has started and will evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent OC patients [283] (Table 5).
Finally, CHK1/2 dual inhibitors, such as prexasertib, have also been developed. Prexasertib (KY2606368 or LY2606368) has shown antitumor activity in HGSC OC cells and HGSC OC patient-derived xenografts. Moreover, its combination with olaparib or gemcitabine induced a synergistic cytotoxic effect [152,153,284]. Several clinical trials are studying the safety and tolerability of prexasertib on OC patients, in monotherapy or in combination with other chemotherapeutic drugs. It has been described that prexasertib treatment was safe and well tolerated and presented preliminary antitumor activity in OC patients [208,209,285]. Its combination with olaparib showed clinical activity in patients that had previously progressed after PARPi treatment [210].

4.2.4. WEE1 Inhibition

Inhibitors of WEE1, a negative regulator of entry into mitosis, have also been developed. Adavosertib (AZD1775 or MK1775), has shown promising results against several tumor cell lines, including OC. In OC cell lines, adavosertib exerted an antitumor activity by inhibiting cell proliferation and migration and inducing DNA damage, apoptosis, and G2/M cell cycle arrest. Moreover, adavosertib activity seemed to be independent of HR repair status [154,286,287]. Patient-derived organoids (PDO) studies showed that this compound could be useful for the treatment of TP53-mutated OC patients [287]. In addition, several studies have proven that adavosertib in combination with other drugs, such as AZD6738 (ATR inhibitor), PF-00477736 (CHK1inhibitor), or radioimmunotherapy, enhanced cytotoxicity obtaining a synergistic cytotoxic effect with combined treatments [155,156,157]. Currently, several clinical trials (phase I and II) are testing the efficacy of adavosertib in combination with other chemotherapeutic drugs, such as gemcitabine, paclitaxel, carboplatin, olaparib, or PLD in OC patients. Adavosertib treatment presented manageable toxicity profiles and its combination with gemcitabine [213], carboplatin with/without paclitaxel [211,212,214], and oaparib [215] could benefit OC patients as summarized in Table 5.

4.3. p53 Pathway

The protein p53 exerts an essential role in the maintenance of genome integrity; it activates some DNA repair proteins when DNA has been damaged, arrests the cell cycle at the G1/S transition allowing DNA repair, and induces apoptosis when DNA damage proves to be irreparable [288]. Because of these essential roles in tumor suppression, p53 is unsurprisingly found mutated in many cancers. In fact, more than 50% of all types of human cancers bear a TP53 mutation [94]. These mutations are especially prevalent in the OC subtype HGSC since they have been identified in 96% of cases [94,95]. Missense mutations in the regions encoding the DNA-binding domains of p53 are the most frequent. They appear in early stages of the disease and are considered driver mutations in ovarian carcinogenesis that can be followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1, or BRCA2 [96].
Several therapeutic strategies have been designed to increase or restore the p53 response in human cancers [289,290]. The most promising are those that try to restore the tumor suppressor protein in cells carrying TP53 gene mutations. PRIMA-1 (also known as APR-017) and its methylated analog PRIMA-1MET (APR-246) are low molecular weight compounds that induce apoptosis in tumor cells by restoring the transcriptional function of mutant p53 [158,291]. PRIMA-1 has shown to induce cell death of OC cells, especially those with mutant p53, and re-sensitized chemoresistant-OC cells with mutant TP53 to cisplatin [158,159]. PRIMA-1MET is a prodrug, which is converted to the active compound methylene quinuclidinone (MQ), that binds to cysteine residues in mutant p53 and restores its wild-type conformation [160]. This agent re-sensitized cisplatin-resistant or doxorubicin-resistant OC cells to cisplatin and doxorubicin, respectively, in vitro and in vivo [160]. In addition, PRIMA-1MET, together with cisplatin/carboplatin/doxorubicin/gemcitabine, exerted a synergistic cytotoxic effect in OC cells [160] that was also observed in primary cancer cells isolated from HGSC OC patients with missense TP53 mutations [160,161]. Its security and effectivity together with PLD/carboplatin have been explored in a phase 1b study in relapsed platinum-sensitive HGSC OC patients [218] (Table 5). Another agent able to restore the p53 function is ReACP53 [162]. This peptide can penetrate tumor cells and inhibit p53 amyloid formation and aggregation, which might rescue p53 function [162,163]. Its preclinical effect in OC cells is detailed in Table 4.
Another way to increase p53 activity is by the inhibition of its negative regulators MDM2/MDM4, that are often overexpressed in tumors WT for TP53. The first molecule identified as a potent inhibitor of the p53-MDM2 interaction was nutlin [292]. The efficacy of this molecule requires WT status of the TP53 gene and intact p53 signaling machinery. In OC, most HGSC tumors harbor mutations of this gene, as previously mentioned; however, CCC or LGSC usually express WT p53 [164]. In vitro experiments in OC TP53 WT cells, found that nutlin reduced cell viability and induced apoptosis [164]. Moreover, it exerted a synergistic cytotoxic effect together with other DNA-damaging drugs and PARPi [165,166,167,168,169,293]. A similar effect was described for other MDM2 inhibitors, such as RG7388 [167,169] and RG7112, which reduced the growth of clear cell tumor cells with intact TP53 both in vitro and in vivo [170].
In summary, we have reviewed the main DDR pathways involved in the maintenance of genome stability; the core DNA repair pathways (DR, MMR, NER, BER, HR, and NHEJ); and the complementary processes that also contribute to overall genome maintenance: cell cycle checkpoints, the p53 pathway, and chromatin remodeling factors. All of them have been found to be altered in OCs either through pathogenic mutations, epigenetic alterations, or polymorphisms in DDR genes. These alterations may contribute to the onset of the disease but also affect sensitivity to therapy. Therefore, considerable efforts are being dedicated to target these defects.

5. Conclusions and Future Perspectives

Alterations in the DDR are commonly observed in OC. The most frequent is HR deficiency (HRD), which has been detected in approximately 50% of epithelial OCs. In 10% of the HGSC subtype, the HRD is caused by germline mutations in the BRCA1/2 genes. These tumors depend on PARP-mediated base excision repair for survival and are selectively killed by PARPi, such as olaparib, that has been approved by the FDA and the EMA for recurrent epithelial OC. In addition to BRCA1 and BRCA2, mutations in other HR genes have been detected in OCs and confer an HR deficiency known as “BRCAness” status. Patients carrying these tumors are also predicted to benefit from the synthetic lethal approach using PARPi. Consequently, several HRD assays have been developed to identify and stratify the patients, although they still have several limitations that need to be solved.
Many different studies, summarized in this review, have also detected other DDR alterations in a variable percentage of OCs, such as defects in DR, MMR, NER, and NHEJ repair pathways, or alterations in chromatin remodelers, checkpoint proteins, and the p53 pathway. Two important elements are needed to specifically target these tumors: biomarkers or reliable functional assays to determine the specific DDR defect in OC samples, and targeted therapies to the associated vulnerabilities. In some cases, laboratory methods could identify the deficiencies (DNA sequencing, determination of MMR or p53 status), but the strategies to specifically target those tumors are not yet available.
Nevertheless, systematic next generation sequencing of individual tumors, or the use or DDR gene panels, will help to not only identify clinically actionable mutations, but also guide patient selection for new clinical studies. In this regard, increasing evidence suggests that cancers with DDR mutations may have high mutational loads and neo-antigens. Therefore, the combination of DDR inhibitors with immunotherapy appears promising to fight these tumors. Defects in the DDR might also be induced by gene silencing through epigenetic mechanisms or by dysregulation of gene function. Reliable functional assays to identify these defects in tumor samples needs to be developed to increase the number of patients that might also respond to DNA damage/repair targeted therapeutic drugs. In addition, more investigation is needed to identify new vulnerabilities associated with specific defects in the DDR and with the acquisition of resistance. These vulnerabilities could be translated into new therapeutic strategies.
Targeting DDR signaling pathways has also become an attractive strategy for increasing the effect of DNA-damaging drugs and overcoming tumor resistance. The idea is to find drug combinations that work in an additive, or better, in a synergistic manner, that is, when the effect of two or more agents working in combination is greater than the expected additive effect. These approaches deserve more investigation since they increase the potential to overcome drug resistance and allow a lower therapeutic dosage of each individual drug, which reduces toxicity. A large number of DDR inhibitors with different potency and selectivity have been developed and are being tested in preclinical and clinical trials. Many of them decrease OC cell proliferation and show synergistic cytotoxic effects in combination with different genotoxic drugs. The challenge ahead is to translate these basic studies into clinical applications that increase the therapeutic arsenal to fight the disease.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15020448/s1. Table S1: PARP inhibitors investigated in clinical studies in monotherapy or in combination with other antitumor drugs [192,198,199,215,216,217,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376].

Author Contributions

Conceptualization, A.B.H.; resources, R.G.-S.; writing—original draft preparation, M.O.-S. and A.B.H.; writing—review and editing, M.O.-S., A.B.H., and R.G.-S.; supervision, A.B.H. and R.G.-S.; funding acquisition, R.G.-S. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the health research program of the “Instituto de Salud Carlos III” (Spanish Ministry of Economy and Competitiveness, PI16/01920 and PI20/01569) co-funded with FEDER funds and project FMM 20/001 (“Fundación Mutua Madrileña”). M.O.-S. was supported by a predoctoral research grant from the Institute of Biomedical Research of Salamanca (IBSAL) (IBpredoc17/00010).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Ray-Coquard, I.; Morice, P.; Lorusso, D.; Prat, J.; Oaknin, A.; Pautier, P.; Colombo, N. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2018, 29, iv1–iv18. [Google Scholar] [CrossRef] [PubMed]
  2. Reid, B.M.; Permuth, J.B.; Sellers, T.A. Epidemiology of ovarian cancer: A review. Cancer Biol. Med. 2017, 14, 9–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Matulonis, U.A.; Sood, A.K.; Fallowfield, L.; Howitt, B.E.; Sehouli, J.; Karlan, B.Y. Ovarian cancer. Nat. Rev. Dis. Prim. 2016, 2, 16061. [Google Scholar] [CrossRef] [PubMed]
  4. Stewart, C.; Ralyea, C.; Lockwood, S. Ovarian Cancer: An Integrated Review. Semin. Oncol. Nurs. 2019, 35, 151–156. [Google Scholar] [CrossRef] [PubMed]
  5. Dion, L.; Carton, I.; Jaillard, S.; Timoh, K.N.; Henno, S.; Sardain, H.; Foucher, F.; Levêque, J.; de la Motte Rouge, T.; Brousse, S.; et al. The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer. J. Clin. Med. 2020, 9, 2239. [Google Scholar] [CrossRef]
  6. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  7. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef] [PubMed]
  8. Dyba, T.; Randi, G.; Bray, F.; Martos, C.; Giusti, F.; Nicholson, N.; Gavin, A.; Flego, M.; Neamtiu, L.; Dimitrova, N.; et al. The European cancer burden in 2020: Incidence and mortality estimates for 40 countries and 25 major cancers. Eur. J. Cancer 2021, 157, 308–347. [Google Scholar] [CrossRef] [PubMed]
  9. Mancari, R.; Cutillo, G.; Bruno, V.; Vincenzoni, C.; Mancini, E.; Baiocco, E.; Bruni, S.; Vocaturo, G.; Chiofalo, B.; Vizza, E. Development of new medical treatment for epithelial ovarian cancer recurrence. Gland. Surg. 2020, 9, 1149–1163. [Google Scholar] [CrossRef]
  10. Van Zyl, B.; Tang, D.; Bowden, N.A. Biomarkers of platinum resistance in ovarian cancer: What can we use to improve treatment. Endocr. Relat. Cancer 2018, 25, R303–R318. [Google Scholar] [CrossRef]
  11. Giornelli, G.H. Management of relapsed ovarian cancer: A review. Springerplus 2016, 5, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Pokhriyal, R.; Hariprasad, R.; Kumar, L.; Hariprasad, G. Chemotherapy Resistance in Advanced Ovarian Cancer Patients. Biomark. Cancer 2019, 11, 1179299X1986081. [Google Scholar] [CrossRef]
  13. Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature 2009, 461, 1071–1078. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Ciccia, A.; Elledge, S.J. The DNA Damage Response: Making It Safe to Play with Knives. Mol. Cell 2010, 40, 179–204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Darzynkiewicz, Z.; Traganos, F.; Wlodkowic, D. Impaired DNA damage response—An Achilles’ heel sensitizing cancer to chemotherapy and radiotherapy. Eur. J. Pharmacol. 2009, 625, 143–150. [Google Scholar] [CrossRef] [Green Version]
  16. Srinivas, U.S.; Tan, B.W.Q.; Vellayappan, B.A.; Jeyasekharan, A.D. ROS and the DNA damage response in cancer. Redox Biol. 2019, 25, 101084. [Google Scholar] [CrossRef]
  17. Kaina, B.; Fritz, G. DNA Damaging Agents. In Encyclopedic Reference of Genomics and Proteomics in Molecular Medicine; Springer: Berlin/Heidelberg, Germany, 2006; pp. 416–423. [Google Scholar] [CrossRef]
  18. Alhmoud, J.F.; Woolley, J.F.; Al Moustafa, A.E.; Malki, M.I. DNA Damage/Repair Management in Cancers. Cancers 2020, 12, 1050. [Google Scholar] [CrossRef]
  19. De Bont, R.; van Larebeke, N. Endogenous DNA damage in humans: A review of quantitative data. Mutagenesis 2004, 19, 169–185. [Google Scholar] [CrossRef] [Green Version]
  20. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 1993, 362, 709–715. [Google Scholar] [CrossRef]
  21. Moretton, A.; Loizou, J.I. Interplay between Cellular Metabolism and the DNA Damage Response in Cancer. Cancers 2020, 12, 2051. [Google Scholar] [CrossRef]
  22. Hoeijmakers, J.H.J. Genome maintenance mechanisms for preventing cancer. Nature 2001, 411, 366–374. [Google Scholar] [CrossRef]
  23. Wogan, G.N.; Hecht, S.S.; Felton, J.S.; Conney, A.H.; Loeb, L.A. Environmental and chemical carcinogenesis. Semin. Cancer Biol. 2004, 14, 473–486. [Google Scholar] [CrossRef]
  24. Gutierrez, R.; O’Connor, T.R. DNA direct reversal repair and alkylating agent drug resistance. Cancer Drug Resist 2021, 4, 414–423. [Google Scholar] [CrossRef]
  25. Pećina-Šlaus, N.; Kafka, A.; Salamon, I.; Bukovac, A. Mismatch Repair Pathway, Genome Stability and Cancer. Front. Mol. Biosci. 2020, 7, 122. [Google Scholar] [CrossRef]
  26. Spivak, G. Nucleotide excision repair in humans. DNA Repair 2015, 36, 13–18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Scully, R.; Panday, A.; Elango, R.; Willis, N.A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 2019, 20, 698–714. [Google Scholar] [CrossRef] [PubMed]
  28. He, B.; Ki, M. The DNA Damage Repair Response. Clin. Oncol. 2020, 3, 1–14. [Google Scholar] [CrossRef]
  29. Acharya, S.; Wilson, T.; Gradia, S.; Kane, M.F.; Guerrette, S.; Marsischky, G.T.; Kolodner, R.; Fishel, R. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc. Natl. Acad. Sci. USA 1996, 93, 13629–13634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Drummond, J.T.; Li, G.-M.; Longley, M.J.; Modrich, P. Isolation of an hMSH2-p160 Heterodimer That Restores DNA Mismatch Repair to Tumor Cells. Science 1995, 268, 1909–1912. [Google Scholar] [CrossRef]
  31. Palombo, F.; Gallinari, P.; Iaccarino, I.; Lettieri, T.; Hughes, M.; D’Arrigo, A.; Truong, O.; Hsuan, J.J.; Jiricny, J. GTBP, a 160-Kilodalton Protein Essential for Mismatch-binding Activity in Human Cells. Science 1995, 268, 1912–1914. [Google Scholar] [CrossRef]
  32. Prindle, M.J.; Loeb, L.A. DNA polymerase delta in DNA replication and genome maintenance. Environ. Mol. Mutagen. 2012, 53, 666–682. [Google Scholar] [CrossRef] [Green Version]
  33. Liu, D.; Keijzers, G.; Rasmussen, L.J. DNA mismatch repair and its many roles in eukaryotic cells. Mutat. Res. Rev. Mutat. Res. 2017, 773, 174–187. [Google Scholar] [CrossRef]
  34. Schärer, O.D. Nucleotide Excision Repair in Eukaryotes. Cold Spring Harb. Perspect. Biol. 2013, 5, a012609. [Google Scholar] [CrossRef] [Green Version]
  35. Lans, H.; Marteijn, J.A.; Vermeulen, W. ATP-dependent chromatin remodeling in the DNA-damage response. Epigenetics Chromatin 2012, 5, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Krokan, H.E.; Bjørås, M. Base Excision Repair. Cold Spring Harb. Perspect. Biol. 2013, 5, a012583. [Google Scholar] [CrossRef] [PubMed]
  37. Marintchev, A.; Robertson, A.; Dimitriadis, E.K.; Prasad, R.; Wilson, S.H.; Mullen, G.P. Domain specific interaction in the XRCC1-DNA polymerase beta complex. Nucleic Acids Res. 2000, 28, 2049–2059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Whitehouse, C.J.; Taylor, R.M.; Thistlethwaite, A.; Zhang, H.; Karimi-Busheri, F.; Lasko, D.D.; Weinfeld, M.; Caldecott, K.W. XRCC1 Stimulates Human Polynucleotide Kinase Activity at Damaged DNA Termini and Accelerates DNA Single-Strand Break Repair. Cell 2001, 104, 107–117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Ford, J.M.; Kastan, M.B. 11 - DNA Damage Response Pathways and Cancer. In Abeloff’s Clinical Oncology, 6th ed.; Elsevier: Amsterdam, The Netherlands, 2020; pp. 154–164.e4. [Google Scholar] [CrossRef]
  40. Wright, W.D.; Shah, S.S.; Heyer, W.-D. Homologous recombination and the repair of DNA double-strand breaks. J. Biol. Chem. 2018, 293, 10524–10535. [Google Scholar] [CrossRef]
  41. Liu, Y.; Lu, L.-Y. BRCA1 and homologous recombination: Implications from mouse embryonic development. Cell Biosci. 2020, 10, 49. [Google Scholar] [CrossRef]
  42. Chen, C.-C.; Feng, W.; Lim, P.X.; Kass, E.M.; Jasin, M. Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer. Annu. Rev. Cancer Biol. 2018, 2, 313–336. [Google Scholar] [CrossRef]
  43. Chang, H.H.Y.; Pannunzio, N.R.; Adachi, N.; Lieber, M.R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 2017, 18, 495–506. [Google Scholar] [CrossRef] [PubMed]
  44. Davis, A.J.; Chen, D.J. DNA double strand break repair via non-homologous end-joining. Transl. Cancer Res. 2013, 2, 130–143. [Google Scholar] [CrossRef]
  45. Caracciolo, D.; Montesano, M.; Tagliaferri, P.; Tassone, P. Alternative non-homologous end joining repair: A master regulator of genomic instability in cancer. Precis. Cancer Med. 2019, 2, 8. [Google Scholar] [CrossRef]
  46. Iliakis, G.; Murmann, T.; Soni, A. Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations. Mutat. Res./Genet. Toxicol. Environ. Mutagen. 2015, 793, 166–175. [Google Scholar] [CrossRef] [PubMed]
  47. Zhang, Z.; Wippo, C.J.; Wal, M.; Ward, E.; Korber, P.; Pugh, B.F. A Packing Mechanism for Nucleosome Organization Reconstituted Across a Eukaryotic Genome. Science 2011, 332, 977–980. [Google Scholar] [CrossRef] [Green Version]
  48. Maréchal, A.; Zou, L. DNA Damage Sensing by the ATM and ATR Kinases. Cold Spring Harb. Perspect. Biol. 2013, 5, a012716. [Google Scholar] [CrossRef]
  49. Zannini, L.; Delia, D.; Buscemi, G. CHK2 kinase in the DNA damage response and beyond. J. Mol. Cell Biol. 2014, 6, 442–457. [Google Scholar] [CrossRef] [Green Version]
  50. Zhang, Y.; Hunter, T. Roles of Chk1 in cell biology and cancer therapy. Int. J. Cancer 2014, 134, 1013–1023. [Google Scholar] [CrossRef]
  51. Roh, H.-J.; Suh, D.-S.; Choi, K.-U.; Yoo, H.-J.; Joo, W.-D.; Yoon, M.-S. Inactivation of O6-methyguanine-DNA methyltransferase by promoter hypermethylation: Association of epithelial ovarian carcinogenesis in specific histological types. J. Obstet. Gynaecol. Res. 2011, 37, 851–860. [Google Scholar] [CrossRef]
  52. Qiao, B.; Zhang, Z.; Li, Y. Association of MGMT promoter methylation with tumorigenesis features in patients with ovarian cancer: A systematic meta-analysis. Mol. Genet. Genom. Med. 2017, 6, 69–76. [Google Scholar] [CrossRef] [Green Version]
  53. Plazzer, J.P.; Sijmons, R.H.; Woods, M.O.; Peltomäki, P.; Thompson, B.; Dunnen, J.T.D.; Macrae, F. The InSiGHT database: Utilizing 100 years of insights into Lynch Syndrome. Fam. Cancer 2013, 12, 175–180. [Google Scholar] [CrossRef] [PubMed]
  54. Jensen, K.C.; Mariappan, M.R.; Putcha, G.V.; Husain, A.; Chun, N.; Ford, J.M.; Schrijver, I.; Longacre, T.A. Microsatellite Instability and Mismatch Repair Protein Defects in Ovarian Epithelial Neoplasms in Patients 50 Years of Age and Younger. Am. J. Surg. Pathol. 2008, 32, 1029–1037. [Google Scholar] [CrossRef] [PubMed]
  55. Watson, P.; Bützow, R.; Lynch, H.T.; Mecklin, J.-P.; Järvinen, H.J.; Vasen, H.F.A.; Madlensky, L.; Fidalgo, P.; Bernstein, I. The Clinical Features of Ovarian Cancer in Hereditary Nonpolyposis Colorectal Cancer. Gynecol. Oncol. 2001, 82, 223–228. [Google Scholar] [CrossRef]
  56. De La Chapelle, A. Microsatellite Instability. N. Engl. J. Med. 2003, 349, 209–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Gras, E.; Catasus, L.; Argü, R.; Moreno-Bueno, G.; Palacios, J.; Gamallo, C.; Matias-Guiu, X.; Prat, J. Microsatellite Instability, MLH-1 Promoter Hypermethylation, and Frameshift Mutations at Coding Mononucleotide Repeat Microsatellites in Ovarian Tumors. Cancer Interdiscip. Int. J. Am. Cancer Soc. 2001, 92, 2829–2836. [Google Scholar] [CrossRef]
  58. Pal, T.; Permuth-Wey, J.; Sellers, T.A. A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer 2008, 113, 733–742. [Google Scholar] [CrossRef] [Green Version]
  59. Zhao, Z.; Zhang, A.; Zhao, Y.; Xiang, J.; Yu, D.; Liang, Z.; Xu, C.; Zhang, Q.; Li, J.; Duan, P. The association of polymorphisms in nucleotide excision repair genes with ovarian cancer susceptibility. Biosci. Rep. 2018, 38, 20180114. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Gee, M.E.; Faraahi, Z.; McCormick, A.; Edmondson, R.J. DNA damage repair in ovarian cancer: Unlocking the heterogeneity. J. Ovarian Res. 2018, 11, 1–12. [Google Scholar] [CrossRef]
  61. Ceccaldi, R.; O’Connor, K.W.; Mouw, K.W.; Li, A.Y.; Matulonis, U.A.; D’Andrea, A.D.; Konstantinopoulos, P.A. A Unique Subset of Epithelial Ovarian Cancers with Platinum Sensitivity and PARP Inhibitor Resistance. Cancer Res 2015, 75, 628–634. [Google Scholar] [CrossRef] [Green Version]
  62. D’Errico, M.; Parlanti, E.; Pascucci, B.; Fortini, P.; Baccarini, S.; Simonelli, V.; Dogliotti, E. Single nucleotide polymorphisms in DNA glycosylases: From function to disease. Free. Radic. Biol. Med. 2017, 107, 278–291. [Google Scholar] [CrossRef] [Green Version]
  63. Chen, X.; Liu, X.; Wang, J.; Guo, W.; Sun, C.; Cai, Z.; Wu, Q.; Xu, X.; Wang, Y. Functional Polymorphisms of the hOGG1 Gene Confer Risk to Type 2 Epithelial Ovarian Cancer in Chinese. Int. J. Gynecol. Cancer 2011, 21, 1407–1413. [Google Scholar] [CrossRef] [PubMed]
  64. Osorio, A.; Milne, R.L.; Kuchenbaecker, K.; Vaclová, T.; Pita, G.; Alonso, R.; Peterlongo, P.; Blanco, I.; de la Hoya, M.; Durán, M.; et al. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. PLOS Genet. 2014, 10, e1004256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Li, K.; Li, W. Association between polymorphisms of XRCC1 and ADPRT genes and ovarian cancer survival with platinum-based chemotherapy in Chinese population. Mol. Cell. Biochem. 2013, 372, 27–33. [Google Scholar] [CrossRef]
  66. Miao, J.; Zhang, X.; Tang, Q.-L.; Wang, X.-Y.; Kai, L. Prediction Value of XRCC 1 Gene Polymorphism on the Survival of Ovarian Cancer Treated by Adjuvant Chemotherapy. Asian Pac. J. Cancer Prev. 2012, 13, 5007–5010. [Google Scholar] [CrossRef] [Green Version]
  67. Malisic, E.J.; Krivokuca, A.M.; Boljevic, I.Z.; Jankovic, R.N. Impact of RAD51 G135C and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women. Cancer Biomarkers 2015, 15, 685–691. [Google Scholar] [CrossRef]
  68. Zhang, X.; Xin, X.; Zhang, J.; Li, J.; Chen, B.; Zou, W. Apurinic/Apyrimidinic Endonuclease 1 Polymorphisms Are Associated with Ovarian Cancer Susceptibility in a Chinese Population. Int. J. Gynecol. Cancer 2013, 23, 1393–1399. [Google Scholar] [CrossRef]
  69. Al-Attar, A.; Gossage, L.; Fareed, K.R.; Shehata, M.; Mohammed, M.; Zaitoun, A.M.; Soomro, I.; Lobo, D.N.; Abbotts, R.; Chan, S.; et al. Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers. Br. J. Cancer 2010, 102, 704–709. [Google Scholar] [CrossRef] [Green Version]
  70. Lin, C.; Liu, P.; Shi, C.; Qiu, L.; Shang, D.; Lu, Z.; Tu, Z.; Liu, H. Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers. Fundam. Clin. Pharmacol. 2022, in press. [Google Scholar] [CrossRef] [PubMed]
  71. Da Cunha Colombo Bonadio, R.R.; Fogace, R.N.; Miranda, V.C.; Diz, M.D.P.E. Homologous recombination deficiency in ovarian cancer: A review of its epidemiology and management. Clinics 2018, 73, e450s. [Google Scholar] [CrossRef]
  72. Zhao, Q.; Yang, J.; Li, L.; Cao, D.; Yu, M.; Shen, K. Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing. J. Gynecol. Oncol. 2017, 28, e39. [Google Scholar] [CrossRef] [Green Version]
  73. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Koczkowska, M.; Krawczynska, N.; Stukan, M.; Kuzniacka, A.; Brozek, I.; Sniadecki, M.; Debniak, J.; Wydra, D.; Biernat, W.; Kozlowski, P.; et al. Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients. Cancers 2018, 10, 442. [Google Scholar] [CrossRef] [Green Version]
  75. Brandt, S.; Samartzis, E.P.; Zimmermann, A.-K.; Fink, D.; Moch, H.; Noske, A.; Dedes, K.J. Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer. BMC Cancer 2017, 17, 44. [Google Scholar] [CrossRef] [Green Version]
  76. Song, H.; Dicks, E.; Ramus, S.J.; Tyrer, J.P.; Intermaggio, M.P.; Hayward, J.; Edlund, C.K.; Conti, D.; Harrington, P.; Fraser, L.; et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J. Clin. Oncol. 2015, 33, 2901–2907. [Google Scholar] [CrossRef] [Green Version]
  77. Zhang, M.; Liu, G.; Xue, F.; Edwards, R.; Sood, A.K.; Zhang, W.; Yang, D. Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer. Gynecol. Oncol. 2016, 141, 57–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Abdel-Fatah, T.M.A.; Arora, A.; Moseley, P.; Coveney, C.; Perry, C.; Johnson, K.; Kent, C.; Ball, G.; Chan, S.; Madhusudan, S. ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers. BBA Clin. 2014, 2, 10–17. [Google Scholar] [CrossRef] [Green Version]
  79. Ceccaldi, R.; Liu, J.C.; Amunugama, R.; Hajdu, I.; Primack, B.; Petalcorin, M.I.R.; O’Connor, K.W.; Konstantinopoulos, P.A.; Elledge, S.J.; Boulton, S.J.; et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 2015, 518, 258–262. [Google Scholar] [CrossRef] [Green Version]
  80. Willis, S.; Villalobos, V.M.; Gevaert, O.; Abramovitz, M.; Williams, C.; Sikic, B.I.; Leyland-Jones, B. Single Gene Prognostic Biomarkers in Ovarian Cancer: A Meta-Analysis. PLoS ONE 2016, 11, e0149183. [Google Scholar] [CrossRef]
  81. Wiegand, K.C.; Shah, S.P.; Al-Agha, O.M.; Zhao, Y.; Tse, K.; Zeng, T.; Senz, J.; McConechy, M.K.; Anglesio, M.S.; Kalloger, S.E.; et al. ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas. N. Engl. J. Med. 2010, 363, 1532–1543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Chen, S.; Li, Y.; Qian, L.; Deng, S.; Liu, L.; Xiao, W.; Zhou, Y. A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer. Front Oncol. 2021, 11, 668151. [Google Scholar] [CrossRef] [PubMed]
  83. Hollis, R.L.; Gourley, C. Genetic and molecular changes in ovarian cancer. Cancer Biol. Med. 2016, 13, 236–247. [Google Scholar] [CrossRef] [Green Version]
  84. Jones, S.; Wang, T.-L.; Shih, I.-M.; Mao, T.-L.; Nakayama, K.; Roden, R.; Glas, R.; Slamon, D.; Diaz, L.A., Jr.; Vogelstein, B.; et al. Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma. Science 2010, 330, 228–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Okawa, R.; Banno, K.; Iida, M.; Yanokura, M.; Takeda, T.; Iijima, M.; Kunitomi-Irie, H.; Nakamura, K.; Adachi, M.; Umene, K.; et al. Aberrant chromatin remodeling in gynecological cancer. Oncol. Lett. 2017, 14, 5107–5113. [Google Scholar] [CrossRef] [Green Version]
  86. Zhao, S.; Choi, M.; Overton, J.D.; Bellone, S.; Roque, D.M.; Cocco, E.; Guzzo, F.; English, D.P.; Varughese, J.; Gasparrini, S.; et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc. Natl. Acad. Sci. USA 2013, 110, 2916–2921. [Google Scholar] [CrossRef] [Green Version]
  87. Le Gallo, M.; O’Hara, A.J.; Rudd, M.L.; Urick, M.E.; Hansen, N.F.; O’Neil, N.J.; Price, J.C.; Zhang, S.; England, B.M.; Godwin, A.K.; et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat. Genet. 2012, 44, 1310–1315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Vaicekauskaitė, I.; Sabaliauskaitė, R.; Lazutka, J.R.; Jarmalaitė, S. The Emerging Role of Chromatin Remodeling Complexes in Ovarian Cancer. Int. J. Mol. Sci. 2022, 23, 13670. [Google Scholar] [CrossRef] [PubMed]
  89. Oyama, Y.; Shigeta, S.; Tokunaga, H.; Tsuji, K.; Ishibashi, M.; Shibuya, Y.; Shimada, M.; Yasuda, J.; Yaegashi, N. CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents. PLoS ONE 2021, 16, e0251079. [Google Scholar] [CrossRef]
  90. Xiao, Y.; Lin, F.-T.; Lin, W.-C. ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer. Proc. Natl. Acad. Sci. USA 2021, 118, e2015808118. [Google Scholar] [CrossRef]
  91. Choi, M.; Kipps, T.; Kurzrock, R. ATM Mutations in Cancer: Therapeutic Implications. Mol. Cancer Ther. 2016, 15, 1781–1791. [Google Scholar] [CrossRef] [Green Version]
  92. Kurian, A.W.; Hughes, E.; Handorf, E.A.; Gutin, A.; Allen, B.; Hartman, A.-R.; Hall, M.J. Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women. JCO Precis. Oncol. 2017, 1, 1–12. [Google Scholar] [CrossRef]
  93. Bartek, J.; Lukas, J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003, 3, 421–429. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Zhang, Y.; Cao, L.; Nguyen, D.; Lu, H. TP53 mutations in epithelial ovarian cancer. Transl. Cancer Res. 2016, 5, 650–663. [Google Scholar] [CrossRef] [PubMed]
  95. Cole, A.J.; Dwight, T.; Gill, A.J.; Dickson, K.-A.; Zhu, Y.; Clarkson, A.; Gard, G.B.; Maidens, J.; Valmadre, S.; Clifton-Bligh, R.; et al. Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing. Sci. Rep. 2016, 6, 26191. [Google Scholar] [CrossRef] [Green Version]
  96. Chien, J.; Sicotte, H.; Fan, J.-B.; Humphray, S.; Cunningham, J.M.; Kalli, K.R.; Oberg, A.L.; Hart, S.N.; Li, Y.; Davila, J.I.; et al. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer. Nucleic Acids Res. 2015, 43, 6945–6958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Barvaux, V.A.; Lorigan, P.; Ranson, M.; Gillum, A.M.; McElhinney, R.S.; McMurry, T.B.H.; Margison, G.P. Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase. Mol. Cancer Ther. 2004, 3, 1215–1220. [Google Scholar] [CrossRef] [PubMed]
  98. Mishra, A.K.; Dormi, S.S.; Turchi, A.M.; Woods, D.S.; Turchi, J.J. Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer. Biochem. Pharmacol. 2015, 93, 25–33. [Google Scholar] [CrossRef] [Green Version]
  99. Musacchio, L.; Cicala, C.M.; Salutari, V.; Camarda, F.; Carbone, M.V.; Ghizzoni, V.; Giudice, E.; Nero, C.; Perri, M.T.; Ricci, C.; et al. Preclinical and Clinical Evidence of Lurbinectedin in Ovarian Cancer: Current Status and Future Perspectives. Front. Oncol. 2022, 12, 585. [Google Scholar] [CrossRef]
  100. Soares, D.G.; Machado, M.S.; Rocca, C.J.; Poindessous, V.; Ouaret, D.; Sarasin, A.; Galmarini, C.M.; Henriques, J.A.P.; Escargueil, A.E.; Larsen, A.K. Trabectedin and Its C Subunit Modified Analogue PM01183 Attenuate Nucleotide Excision Repair and Show Activity toward Platinum-Resistant Cells. Mol. Cancer Ther. 2011, 10, 1481–1489. [Google Scholar] [CrossRef] [PubMed]
  101. Vidal, A.; Muñoz, C.; Guillén, M.-J.; Moretó, J.; Puertas, S.; Martínez-Iniesta, M.; Figueras, A.; Padullés, L.; García-Rodriguez, F.J.; Berdiel-Acer, M.; et al. Lurbinectedin (PM01183), a New DNA Minor Groove Binder, Inhibits Growth of Orthotopic Primary Graft of Cisplatin-Resistant Epithelial Ovarian Cancer. Clin. Cancer Res. 2012, 18, 5399–5411. [Google Scholar] [CrossRef] [Green Version]
  102. D’Incalci, M.; Colombo, T.; Ubezio, P.; Nicoletti, I.; Giavazzi, R.; Erba, E.; Ferrarese, L.; Meco, D.; Riccardi, R.; Sessa, C.; et al. The combination of yondelis and cisplatin is synergistic against human tumor xenografts. Eur. J. Cancer 2003, 39, 1920–1926. [Google Scholar] [CrossRef]
  103. Fishel, M.L.; He, Y.; Smith, M.L.; Kelley, M.R. Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide. Clin. Cancer Res. 2007, 13, 260–267. [Google Scholar] [CrossRef] [Green Version]
  104. Luo, M.; Delaplane, S.; Jiang, A.; Reed, A.; He, Y.; Fishel, M.; Nyland, R.L.; Borch, R.F.; Qiao, X.; Georgiadis, M.M.; et al. Role of the Multifunctional DNA Repair and Redox Signaling Protein Ape1/Ref-1 in Cancer and Endothelial Cells: Small-Molecule Inhibition of the Redox Function of Ape1. Antioxid. Redox Signal. 2008, 10, 1853–1867. [Google Scholar] [CrossRef] [PubMed]
  105. Kelley, M.R.; Luo, M.; Reed, A.; Su, D.; Delaplane, S.; Borch, R.F.; Nyland, R.L.; Gross, M.L.; Georgiadis, M.M. Functional Analysis of Novel Analogues of E3330 That Block the Redox Signaling Activity of the Multifunctional AP Endonuclease/Redox Signaling Enzyme APE1/Ref-1. Antioxid. Redox Signal. 2011, 14, 1387–1401. [Google Scholar] [CrossRef] [PubMed]
  106. Poletto, M.; Malfatti, M.C.; Dorjsuren, D.; Scognamiglio, P.L.; Marasco, D.; Vascotto, C.; Jadhav, A.; Maloney, D.J.; Wilson, D.M.; Simeonov, A.; et al. Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti-tumor properties. Mol. Carcinog. 2015, 55, 688–704. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434, 913–917. [Google Scholar] [CrossRef]
  108. Farmer, H.; McCabe, N.; Lord, C.J.; Tutt, A.N.J.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J.; Hickson, I.; Knights, C.; et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434, 917–921. [Google Scholar] [CrossRef]
  109. Ovejero-Sánchez, M.; González-Sarmiento, R.; Herrero, A.B. Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair. Neoplasia 2021, 23, 515–528. [Google Scholar] [CrossRef]
  110. Alblihy, A.; Ali, R.; Algethami, M.; Shoqafi, A.; Toss, M.S.; Brownlie, J.; Tatum, N.J.; Hickson, I.; Moran, P.O.; Grabowska, A.; et al. Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian cancers. NPJ Precis. Oncol. 2022, 6, 1–12. [Google Scholar] [CrossRef]
  111. Huang, D.; Chowdhury, S.; Wang, H.; Savage, S.R.; Ivey, R.G.; Kennedy, J.J.; Whiteaker, J.R.; Lin, C.; Hou, X.; Oberg, A.L.; et al. Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer. Cell Rep. Med. 2021, 2, 100471. [Google Scholar] [CrossRef]
  112. Wilson, A.J.; Sarfo-Kantanka, K.; Barrack, T.; Steck, A.; Saskowski, J.; Crispens, M.A.; Khabele, D. Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib. Gynecol. Oncol. 2016, 143, 143–151. [Google Scholar] [CrossRef] [Green Version]
  113. Helland, Ø.; Popa, M.; Bischof, K.; Gjertsen, B.T.; Mc Cormack, E.; Bjørge, L. The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer. PLoS ONE 2016, 11, e0158208. [Google Scholar] [CrossRef] [Green Version]
  114. Ma, Y.-Y.; Lin, H.; Moh, J.-S.; Chen, K.-D.; Wang, I.-W.; Ou, Y.-C.; You, Y.-S.; Lung, C.-C. Low-dose LBH589 increases the sensitivity of cisplatin to cisplatin-resistant ovarian cancer cells. Taiwan. J. Obstet. Gynecol. 2011, 50, 165–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Liu, H.; Zeng, Z.; Wang, S.; Li, T.; Mastriani, E.; Li, Q.-H.; Bao, H.-X.; Zhou, Y.-J.; Wang, X.; Liu, Y.; et al. Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biol. Ther. 2017, 18, 990–999. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Ovejero-Sánchez, M.; Rubio-Heras, J.; Peña, M.d.C.V.d.l.; San-Segundo, L.; Pérez-Losada, J.; González-Sarmiento, R.; Herrero, A.B. Chloroquine-Induced DNA Damage Synergizes with Nonhomologous End Joining Inhibition to Cause Ovarian Cancer Cell Cytotoxicity. Int. J. Mol. Sci. 2022, 23, 7518. [Google Scholar] [CrossRef] [PubMed]
  117. Nutley, B.P.; Smith, N.F.; Hayes, A.; Kelland, L.R.; Brunton, L.; Golding, B.T.; Smith, G.C.M.; Martin, N.M.B.; Workman, P.; Raynaud, F.I. Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Br. J. Cancer 2005, 93, 1011–1018. [Google Scholar] [CrossRef] [Green Version]
  118. Stronach, E.A.; Chen, M.; Maginn, E.N.; Agarwal, R.; Mills, G.B.; Wasan, H.; Gabra, H. DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance. Neoplasia 2011, 13, 1069–1080. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Matsumoto, Y. Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy. Int. J. Mol. Sci. 2022, 23, 4264. [Google Scholar] [CrossRef]
  120. Haines, E.; Nishida, Y.; Carr, M.I.; Montoya, R.H.; Ostermann, L.B.; Zhang, W.G.; Zenke, F.T.; Blaukat, A.; Andreeff, M.; Vassilev, L.T. DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia. Sci Rep-Uk 2021, 11. [Google Scholar] [CrossRef]
  121. Ramos-Montoya, A.; Fok, J.H.; James, N.; Follia, V.; Vazquez-Chantada, M.; Wijnhoven, P.; O’Connor, L.O.; Karmokar, A.; Staniszewska, A.; Dean, E.; et al. AZD7648, a potent and selective inhibitor of DNA-PK, potentiates activity of the PARP inhibitor olaparib resulting in sustained anti-tumour activity in xenograft and PDX models. Cancer Res 2019, 79. [Google Scholar] [CrossRef]
  122. Anastasia, A.; Dellavedova, G.; Ramos-Montoya, A.; James, N.; Chiorino, G.; Russo, M.; Baakza, H.; Wilson, J.; Ghilardi, C.; Cadogan, E.B.; et al. The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases. Mol. Cancer Ther. 2022, 21, 555–567. [Google Scholar] [CrossRef]
  123. Wang, N.; Yu, M.; Fu, Y.; Ma, Z. Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via Hsa-MiR-542-5p. Front. Oncol. 2022, 12, 2934. [Google Scholar] [CrossRef] [PubMed]
  124. Teng, P.-N.; Bateman, N.W.; Darcy, K.M.; Hamilton, C.A.; Maxwell, G.L.; Bakkenist, C.J.; Conrads, T.P. Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells. Gynecol. Oncol. 2015, 136, 554–561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Lima, M.; Bouzid, H.; Soares, D.G.; Selle, F.; Morel, C.; Galmarini, C.M.; Henriques, J.A.P.; Larsen, A.K.; Escargueil, A.E. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair. Oncotarget 2016, 7, 25885–25901. [Google Scholar] [CrossRef] [PubMed]
  126. Grimley, E.; Cole, A.J.; Luong, T.T.; McGonigal, S.C.; Sinno, S.; Yang, D.; Bernstein, K.A.; Buckanovich, R.J. Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM/ATR inhibitors. Theranostics 2021, 11, 3540–3551. [Google Scholar] [CrossRef] [PubMed]
  127. Bradbury, A.; Zenke, F.T.; Curtin, N.J.; Drew, Y. The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response. Cells 2022, 11, 2361. [Google Scholar] [CrossRef] [PubMed]
  128. Huntoon, C.J.; Flatten, K.S.; Hendrickson, A.E.W.; Huehls, A.M.; Sutor, S.L.; Kaufmann, S.H.; Karnitz, L.M. ATR Inhibition Broadly Sensitizes Ovarian Cancer Cells to Chemotherapy Independent of BRCA Status. Cancer Res 2013, 73, 3683–3691. [Google Scholar] [CrossRef] [Green Version]
  129. Williamson, C.T.; Miller, R.; Pemberton, H.N.; Jones, S.E.; Campbell, J.; Konde, A.; Badham, N.; Rafiq, R.; Brough, R.; Gulati, A.; et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat. Commun. 2016, 7, 13837. [Google Scholar] [CrossRef] [Green Version]
  130. Smith, H.L.; Willmore, E.; Mukhopadhyay, A.; Drew, Y.; Curtin, N.J. Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling. cancers 2022, 22, 5559. [Google Scholar] [CrossRef]
  131. Yazinski, S.A.; Comaills, V.; Buisson, R.; Genois, M.-M.; Nguyen, H.D.; Ho, C.K.; Kwan, T.T.; Morris, R.; Lauffer, S.; Nussenzweig, A.; et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev. 2017, 31, 318–332. [Google Scholar] [CrossRef] [Green Version]
  132. Hur, J.; Ghosh, M.; Kim, T.H.; Park, N.; Pandey, K.; Cho, Y.B.; Hong, S.D.; Katuwal, N.B.; Kang, M.; An, H.J.; et al. Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer. Int. J. Mol. Sci. 2021, 22, 1223. [Google Scholar] [CrossRef]
  133. Kim, H.; George, E.; Ragland, R.L.; Rafail, S.; Zhang, R.; Krepler, C.; Morgan, M.A.; Herlyn, M.; Brown, E.J.; Simpkins, F. Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models. Clin. Cancer Res. 2017, 23, 3097–3108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Kim, H.; Xu, H.; George, E.; Hallberg, D.; Kumar, S.; Jagannathan, V.; Medvedev, S.; Kinose, Y.; Devins, K.; Verma, P.; et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat. Commun. 2020, 11, 3726. [Google Scholar] [CrossRef] [PubMed]
  135. Wilson, Z.; Odedra, R.; Wallez, Y.; Wijnhoven, P.W.G.; Hughes, A.M.; Gerrard, J.; Jones, G.N.; Bargh-Dawson, H.; Brown, E.; Young, L.A.; et al. ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib. Cancer Res 2022, 82, 1140–1152. [Google Scholar] [CrossRef]
  136. Feng, W.; Dean, D.C.; Hornicek, F.J.; Wang, J.; Jia, Y.; Duan, Z.; Shi, H. ATR and p-ATR are emerging prognostic biomarkers and DNA damage response targets in ovarian cancer. Ther. Adv. Med. Oncol. 2020, 12, 1–18. [Google Scholar] [CrossRef]
  137. Hill, S.J.; Decker, B.; Roberts, E.A.; Horowitz, N.S.; Muto, M.G.; Worley, M.J.; Feltmate, C.M.; Nucci, M.R.; Swisher, E.M.; Nguyen, H.; et al. Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids. Cancer Discov. 2018, 8, 1404–1421. [Google Scholar] [CrossRef] [Green Version]
  138. Peasland, A.; Wang, L.-Z.; Rowling, E.; Kyle, S.; Chen, T.; Hopkins, A.; Cliby, W.A.; Sarkaria, J.; Beale, G.; Edmondson, R.J.; et al. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br. J. Cancer 2011, 105, 372–381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Siemeister, G.; Mengel, A.; Fernández-Montalván, A.E.; Bone, W.; Schröder, J.; Zitzmann-Kolbe, S.; Briem, H.; Prechtl, S.; Holton, S.J.; Mönning, U.; et al. Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo. Clin. Cancer Res. 2019, 25, 1404–1414. [Google Scholar] [CrossRef] [Green Version]
  140. Wengner, A.M.; Siemeister, G.; Lücking, U.; Lefranc, J.; Wortmann, L.; Lienau, P.; Bader, L.P.B.; Bömer, U.; Moosmayer, D.; Eberspächer, U.; et al. The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models. Mol. Cancer Ther. 2020, 19, 26–38. [Google Scholar] [CrossRef]
  141. Wickstroem, K.; Hagemann, U.B.; Cruciani, V.; Wengner, A.M.; Kristian, A.; Ellingsen, C.; Siemeister, G.; Bjerke, R.M.; Karlsson, J.; Ryan, O.B.; et al. Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models. J. Nucl. Med. 2019, 60, 1293–1300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Jo, U.; Senatorov, I.S.; Zimmermann, A.; Saha, L.K.; Murai, Y.; Kim, S.H.; Rajapakse, V.N.; Elloumi, F.; Takahashi, N.; Schultz, C.W.; et al. Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents. Mol. Cancer Ther. 2021, 20, 1431–1441. [Google Scholar] [CrossRef] [PubMed]
  143. Booth, L.; Roberts, J.; Poklepovic, A.; Dent, P. The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells. Cancer Biol. Ther. 2018, 19, 786–796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Bryant, C.; Rawlinson, R.; Massey, A.J. Chk1 Inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers. BMC Cancer 2014, 14, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Burgess, B.T.; Anderson, A.M.; McCorkle, J.R.; Wu, J.; Ueland, F.R.; Kolesar, J.M. Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells. Diagnostics 2020, 10, 121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Kim, M.K.; James, J.; Annunziata, C.M. Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells. BMC Cancer 2015, 15, 196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Jobson, A.G.; Lountos, G.T.; Lorenzi, P.L.; Llamas, J.; Connelly, J.; Cerna, D.; Tropea, J.E.; Onda, A.; Zoppoli, G.; Kondapaka, S.; et al. Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]. J. Pharmacol. Exp. Ther. 2009, 331, 816–826. [Google Scholar] [CrossRef] [Green Version]
  148. Han, J.H.-J.; Kim, K.-T.; Im, J.; Park, S.; Choi, M.K.; Kim, I.; Nam, K.-Y.; Yoon, J. Abstract 1461: PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells. Cancer Res 2021, 81, 1461. [Google Scholar] [CrossRef]
  149. Liang, X.; Guo, Y.; Figg, W.D.; Fojo, A.T.; Mueller, M.D.; Yu, J.J. The Role of Wild-Type p53 in Cisplatin-Induced Chk2 Phosphorylation and the Inhibition of Platinum Resistance with a Chk2 Inhibitor. Chemother. Res. Pr. 2011, 2011, 1–8. [Google Scholar] [CrossRef]
  150. Itamochi, H.; Nishimura, M.; Oumi, N.; Kato, M.; Oishi, T.; Shimada, M.; Sato, S.; Naniwa, J.; Sato, S.; Kudoh, A.; et al. Checkpoint Kinase Inhibitor AZD7762 Overcomes Cisplatin Resistance in Clear Cell Carcinoma of the Ovary. Int. J. Gynecol. Cancer 2014, 24, 61–69. [Google Scholar] [CrossRef]
  151. Pillay, N.; Tighe, A.; Nelson, L.; Littler, S.; Coulson-Gilmer, C.; Bah, N.; Golder, A.; Bakker, B.; Spierings, D.C.; James, D.I.; et al. DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors. Cancer Cell 2019, 35, 519–533.e8. [Google Scholar] [CrossRef] [Green Version]
  152. Parmar, K.; Kochupurakkal, B.S.; Lazaro, J.-B.; Wang, Z.C.; Palakurthi, S.; Kirschmeier, P.T.; Yang, C.; Sambel, L.A.; Färkkilä, A.; Reznichenko, E.; et al. The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition. Clin. Cancer Res. 2019, 25, 6127–6140. [Google Scholar] [CrossRef]
  153. Brill, E.; Yokoyama, T.; Nair, J.; Yu, M.; Ahn, Y.-R.; Lee, J.-M. Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases in vitro toxicity of PARP inhibition by preventing Rad51 foci formation in BRCA wild type high-grade serous ovarian cancer. Oncotarget 2017, 8, 111026–111040. [Google Scholar] [CrossRef]
  154. Roering, P.; Siddiqui, A.; Heuser, V.D.; Potdar, S.; Mikkonen, P.; Oikkonen, J.; Li, Y.; Pikkusaari, S.; Wennerberg, K.; Hynninen, J.; et al. Effects of Wee1 inhibitor adavosertib on patient-derived high-grade serous ovarian cancer cells are multiple and independent of homologous recombination status. Front. Oncol. 2022, 12, 1–14. [Google Scholar] [CrossRef] [PubMed]
  155. Wu, X.; Kang, X.; Zhang, X.; Xie, W.; Su, Y.; Liu, X.; Guo, L.; Guo, E.; Li, F.; Hu, D.; et al. WEE1 inhibitor and ataxia telangiectasia and RAD3-related inhibitor trigger stimulator of interferon gene-dependent immune response and enhance tumor treatment efficacy through programmed death-ligand 1 blockade. Cancer Sci. 2021, 112, 4444–4456. [Google Scholar] [CrossRef] [PubMed]
  156. Carrassa, L.; Chilà, R.; Lupi, M.; Ricci, F.; Celenza, C.; Mazzoletti, M.; Broggini, M.; Damia, G. Combined inhibition of Chk1 and Wee1: In vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle 2012, 11, 2507–2517. [Google Scholar] [CrossRef] [Green Version]
  157. Lindenblatt, D.; Terraneo, N.; Pellegrini, G.; Cohrs, S.; Spycher, P.R.; Vukovic, D.; Béhé, M.; Schibli, R.; Grünberg, J. Combination of lutetium-177 labelled anti-L1CAM antibody chCE7 with the clinically relevant protein kinase inhibitor MK1775: A novel combination against human ovarian carcinoma. BMC Cancer 2018, 18, 922. [Google Scholar] [CrossRef] [Green Version]
  158. Kobayashi, N.; Abedini, M.; Sakuragi, N.; Tsang, B.K. PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: A requirement for Akt down-regulation. J. Ovarian Res. 2013, 6, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  159. Bykov, V.J.N.; Issaeva, N.; Selivanova, G.; Wiman, K.G. Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: A statistical analysis of information in the National Cancer Institute database. Carcinogenesis 2002, 23, 2011–2018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Mohell, N.; Alfredsson, J.; Fransson, A.; Uustalu, M.; Bystrom, S.; Gullbo, J.; Hallberg, A.; Bykov, V.J.N.; Bjorklund, U.; Wiman, K.G. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis. 2015, 6, e1794. [Google Scholar] [CrossRef] [PubMed]
  161. Fransson, Å.; Glaessgen, D.; Alfredsson, J.; Wiman, K.G.; Bajalica-Lagercrantz, S.; Mohell, N. Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer. J. Ovarian Res. 2016, 9, 1–10. [Google Scholar] [CrossRef] [Green Version]
  162. Soragni, A.; Janzen, D.M.; Johnson, L.M.; Lindgren, A.G.; Nguyen, A.T.-Q.; Tiourin, E.; Soriaga, A.B.; Lu, J.; Jiang, L.; Faull, K.F.; et al. A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas. Cancer Cell 2016, 29, 90–103. [Google Scholar] [CrossRef] [Green Version]
  163. Neal, A.; Lai, T.; Singh, T.; Rahseparian, N.; Grogan, T.; Elashoff, D.; Scott, P.; Pellegrini, M.; Memarzadeh, S. Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers. Cancers 2021, 13, 5908. [Google Scholar] [CrossRef]
  164. Crane, E.K.; Kwan, S.-Y.; Izaguirre, D.I.; Tsang, Y.T.M.; Mullany, L.K.; Zu, Z.; Richards, J.S.; Gershenson, D.M.; Wong, K.-K. Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas. PLoS ONE 2015, 10, e0135101. [Google Scholar] [CrossRef] [PubMed]
  165. Meijer, A.J.; Kruyt, F.A.E.; Van Der Zee, A.G.J.; Hollema, H.; Le, P.; Hoor, K.A.T.; Groothuis, G.M.M.; Quax, W.J.; de Vries, E.G.E.; De Jong, S. Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL. Br. J. Cancer 2013, 109, 2685–2695. [Google Scholar] [CrossRef] [PubMed]
  166. Xie, X.; He, G.; Siddik, Z.H. Cisplatin in Combination with MDM2 Inhibition Downregulates Rad51 Recombinase in a Bimodal Manner to Inhibit Homologous Recombination and Augment Tumor Cell Kill. Mol. Pharmacol. 2020, 97, 237–249. [Google Scholar] [CrossRef] [PubMed]
  167. Zanjirband, M.; Edmondson, R.J.; Lunec, J. Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer. Oncotarget 2016, 7, 40115–40134. [Google Scholar] [CrossRef] [Green Version]
  168. Mir, R.; Tortosa, A.; Martinez-Soler, F.; Vidal, A.; Condom, E.; Pérez-Perarnau, A.; Ruiz-Larroya, T.; Gil, J.; Giménez-Bonafé, P. Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance inTP53wild-type ovarian cancer cells. Int. J. Cancer 2013, 132, 1525–1536. [Google Scholar] [CrossRef] [PubMed]
  169. Zanjirband, M.; Curtin, N.; Edmondson, R.J.; Lunec, J. Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer. Oncotarget 2017, 8, 69779–69796. [Google Scholar] [CrossRef]
  170. Makii, C.; Oda, K.; Ikeda, Y.; Sone, K.; Hasegawa, K.; Uehara, Y.; Nishijima, A.; Asada, K.; Koso, T.; Fukuda, T.; et al. MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53. Oncotarget 2016, 7, 75328–75338. [Google Scholar] [CrossRef]
  171. Ranson, M.; Middleton, M.R.; Bridgewater, J.; Lee, S.M.; Dawson, M.; Jowle, D.; Halbert, G.; Waller, S.; McGrath, H.; Gumbrell, L.; et al. Lomeguatrib, a Potent Inhibitor of O6-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2006, 12, 1577–1584. [Google Scholar] [CrossRef] [Green Version]
  172. Del Campo, J.M.; Roszak, A.; Bidzinski, M.; Ciuleanu, T.E.; Hogberg, T.; Wojtukiewicz, M.Z.; Poveda, A.; Boman, K.; Westermann, A.M.; Lebedinsky, C. Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer. Ann. Oncol. 2009, 20, 1794–1802. [Google Scholar] [CrossRef]
  173. Thertulien, R.; Manikhas, G.M.; Dirix, L.Y.; Vermorken, J.B.; Park, K.; Jain, M.M.; Jiao, J.J.; Natarajan, J.; Parekh, T.; Zannikos, P.; et al. Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies. Cancer Chemother. Pharmacol. 2012, 69, 341–350. [Google Scholar] [CrossRef] [Green Version]
  174. Yovine, A.; Riofrio, M.; Blay, J.-Y.; Brain, E.; Alexandre, J.; Kahatt, C.; Taamma, A.; Jimeno, J.; Martin, C.; Salhi, Y.; et al. Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients. J. Clin. Oncol. 2004, 22, 890–899. [Google Scholar] [CrossRef]
  175. Lorusso, D.; Pignata, S.; Tamberi, S.; Mangili, G.; Bologna, A.; Nicoloso, M.S.; Giolitto, S.; Salutari, V.; Mantero, M.; Pisano, C.; et al. Efficacy and safety of trabectedin for the treatment of advanced uterine or ovarian carcinosarcoma: Results of a phase II multicenter clinical trial (MITO-26). Gynecol. Oncol. 2022, 167, 436–443. [Google Scholar] [CrossRef]
  176. Lorusso, D.; Scambia, G.; Pignata, S.; Sorio, R.; Amadio, G.; Lepori, S.; Mosconi, A.; Pisano, C.; Mangili, G.; Maltese, G.; et al. Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: The MITO 15 trial. Ann. Oncol. 2016, 27, 487–493. [Google Scholar] [CrossRef] [PubMed]
  177. Scambia, G.; Raspagliesi, F.; Valabrega, G.; Colombo, N.; Pisano, C.; Cassani, C.; Tognon, G.; Tamberi, S.; Mangili, G.; Mammoliti, S.; et al. Randomized phase III trial on trabectedin (ET-743) single agent versus clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal, or fallopian tube cancers of BRCA-mutated or BRCAness phenotype patients (MITO23). J. Clin. Oncol. 2022, 40, LBA5504. [Google Scholar] [CrossRef]
  178. Colombo, N.; Gadducci, A.; Sehouli, J.; Biagioli, E.; Nyvang, G.-B.; Riniker, S.; Montes, A.; Ottevanger, N.; Zeimet, A.G.G.; Vergote, I.B.; et al. LBA30 INOVATYON study: Randomized phase III international study comparing trabectedin/PLD followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6–12 months after last platinum line. Ann. Oncol. 2020, 31, S1161. [Google Scholar] [CrossRef]
  179. Jones, R.L.; Herzog, T.J.; Patel, S.R.; von Mehren, M.; Schuetze, S.M.; Van Tine, B.A.; Coleman, R.L.; Knoblauch, R.; Triantos, S.; Hu, P.; et al. Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer. Cancer Med. 2021, 10, 3565–3574. [Google Scholar] [CrossRef]
  180. Krasner, C.N.; Poveda, A.; Herzog, T.J.; Vermorken, J.B.; Kaye, S.B.; Nieto, A.; Claret, P.L.; Park, Y.C.; Parekh, T.; Monk, B.J. Patient-reported outcomes in relapsed ovarian cancer: Results from a randomized Phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD Alone. Gynecol. Oncol. 2012, 127, 161–167. [Google Scholar] [CrossRef]
  181. Monk, B.J.; Herzog, T.J.; Wang, G.; Triantos, S.; Maul, S.; Knoblauch, R.; McGowan, T.; Shalaby, W.S.W.; Coleman, R.L. A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer. Gynecol. Oncol. 2020, 156, 535–544. [Google Scholar] [CrossRef] [PubMed]
  182. Monk, B.J.; Herzog, T.J.; Kaye, S.B.; Krasner, C.N.; Vermorken, J.B.; Muggia, F.M.; Pujade-Lauraine, E.; Park, Y.C.; Parekh, T.V.; Poveda, A.M. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival analysis. Eur. J. Cancer 2012, 48, 2361–2368. [Google Scholar] [CrossRef]
  183. Chekerov, R.; Deryal, M.; Aktas, B.; Röhle, R.; Stürzebecher, A.; Battista, M.J.; Kurbacher, C.M.; Wimberger, P.; Lorenz, R.; Barinoff, J.; et al. 2022-RA-672-ESGO Comparison of quality of life in patients with platinum-sensitive recurrent ovarian, fallopian tube and peritoneal cancer treated with trabectedin plus pegylated liposomal doxorubicin (PLD) or standard platinum-based therapy: Data look of the NOGGO S16/COMPASS trial. Int. J. Gynecol. Cancer 2022, 32, A252–A253. [Google Scholar] [CrossRef]
  184. Romero, I.; Mallol, P.; Santaballa, A.; Del Campo, J.M.; Mori, M.; González-Santiago, S.; Casado, A.; Vicente, D.; Ortega, E.; Herrero, A.; et al. Multicenter retrospective study to evaluate the impact of trabectedin plus pegylated liposomal doxorubicin on the subsequent treatment in women with recurrent, platinum-sensitive ovarian cancer. Anti-Cancer Drugs 2019, 30, 628–635. [Google Scholar] [CrossRef] [PubMed]
  185. Pignata, S.; Scambia, G.; Villanucci, A.; Naglieri, E.; Ibarbia, M.A.; Brusa, F.; Bourgeois, H.; Sorio, R.; Casado, A.; Reichert, D.; et al. A European, Observational, Prospective Trial of Trabectedin Plus Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Ovarian Cancer. Oncologist 2021, 26, e658–e668. [Google Scholar] [CrossRef] [PubMed]
  186. Selle, F.; Heudel, P.-E.; Hardy-Bessard, A.-C.; Pozet, A.; Meunier, J.; Gladieff, L.; Lotz, J.-P.; Provansal, M.; Augereau, P.; Berton, D.; et al. GINECO Prospective Non-interventional PROSPECTYON Study: Trabectedin Plus Pegylated Liposomal Doxorubicin for Platinum-sensitive Recurrent Ovarian Cancer. Anticancer. Res. 2020, 40, 3939–3945. [Google Scholar] [CrossRef] [PubMed]
  187. Runnebaum, I.B.; Reichert, D.; Ringsdorf, U.; Kuther, M.; Hesse, T.; Sehouli, J.; Wimberger, P. Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: A prospective, observational, multicenter study. J. Cancer Res. Clin. Oncol. 2018, 144, 1185–1195. [Google Scholar] [CrossRef] [Green Version]
  188. Toulmonde, M.; Brahmi, M.; Giraud, A.; Chakiba, C.; Bessede, A.; Kind, M.; Toulza, E.; Pulido, M.; Albert, S.; Guégan, J.-P.; et al. Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study. Clin. Cancer Res. 2022, 28, 1765–1772. [Google Scholar] [CrossRef]
  189. Monk, B.J.; Sill, M.W.; Hanjani, P.; Edwards, R.; Rotmensch, J.; De Geest, K.; Bonebrake, A.J.; Walker, J.L. Docetaxel plus trabectedin appears active in recurrent or persistent ovarian and primary peritoneal cancer after up to three prior regimens: A phase II study of the Gynecologic Oncology Group. Gynecol. Oncol. 2011, 120, 459–463. [Google Scholar] [CrossRef]
  190. Colombo, N.; Zaccarelli, E.; Baldoni, A.; Frezzini, S.; Scambia, G.; Palluzzi, E.; Tognon, G.; Lissoni, A.A.; Rubino, D.; Ferrero, A.; et al. Multicenter, randomised, open-label, non-comparative phase 2 trial on the efficacy and safety of the combination of bevacizumab and trabectedin with or without carboplatin in women with partially platinum-sensitive recurrent ovarian cancer. Br. J. Cancer 2019, 121, 744–750. [Google Scholar] [CrossRef]
  191. Calvo, E.; Sessa, C.; Harada, G.; de Miguel, M.; Kahatt, C.; Luepke-Estefan, X.E.; Siguero, M.; Fernandez-Teruel, C.; Cullell-Young, M.; Stathis, A.; et al. Phase I study of lurbinectedin in combination with weekly paclitaxel with or without bevacizumab in patients with advanced solid tumors. Investig. New Drugs 2022, 40, 1263–1273. [Google Scholar] [CrossRef]
  192. Poveda, A.; Oaknin, A.; Romero, I.; Guerrero, A.; Fariñas-Madrid, L.; Rodriguez-Freixinos, V.; Soto-Matos, A.; Peris, C.; Teruel, M.; Lopez-Reig, R.; et al. Phase I study to evaluate the tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) of PM01183 (Lurbinectedin) in combination with olaparib in patients with advanced solid tumors. J. Clin. Oncol. 2017, 35, 5573. [Google Scholar] [CrossRef]
  193. Cortesi, L.; Venturelli, M.; Barbieri, E.; Baldessari, C.; Bardasi, C.; Coccia, E.; Baglio, F.; Rimini, M.; Greco, S.; Napolitano, M.; et al. Exceptional response to lurbinectedin and irinotecan in BRCA-mutated platinum-resistant ovarian cancer patient: A case report. Ther. Adv. Chronic Dis. 2022, 13, 20406223211063023. [Google Scholar] [CrossRef]
  194. Gaillard, S.; Oaknin, A.; Ray-Coquard, I.; Vergote, I.; Scambia, G.; Colombo, N.; Fernandez, C.; Alfaro, V.; Kahatt, C.; Nieto, A.; et al. Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL). Gynecol. Oncol. 2021, 163, 237–245. [Google Scholar] [CrossRef] [PubMed]
  195. Coyne, G.O.; Kummar, S.; Meehan, R.S.; Do, K.; Collins, J.M.; Anderson, L.; Ishii, K.; Takebe, N.; Zlott, J.; Juwara, L.; et al. Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas. Oncotarget 2020, 11, 3959–3971. [Google Scholar] [CrossRef] [PubMed]
  196. Morita, S.; Oizumi, S.; Minami, H.; Kitagawa, K.; Komatsu, Y.; Fujiwara, Y.; Inada, M.; Yuki, S.; Kiyota, N.; Mitsuma, A.; et al. Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors. Investig. New Drugs 2012, 30, 1950–1957. [Google Scholar] [CrossRef] [PubMed]
  197. Jones, S.F.; Infante, J.R.; Thompson, D.S.; Mohyuddin, A.; Bendell, J.C.; Yardley, D.A.; Burris, H.A. A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother. Pharmacol. 2012, 70, 471–475. [Google Scholar] [CrossRef]
  198. Shah, P.D.; Wethington, S.L.; Pagan, C.; Latif, N.; Tanyi, J.; Martin, L.P.; Morgan, M.; Burger, R.A.; Haggerty, A.; Zarrin, H.; et al. Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol. Oncol. 2021, 163, 246–253. [Google Scholar] [CrossRef] [PubMed]
  199. Mahdi, H.; Hafez, N.; Doroshow, D.; Sohal, D.; Keedy, V.; Do, K.T.; LoRusso, P.; Jürgensmeier, J.; Avedissian, M.; Sklar, J.; et al. Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). JCO Precis. Oncol. 2021, 5, 1432–1442. [Google Scholar] [CrossRef] [PubMed]
  200. Banerjee, S.; Vergotte, I.; Colombo, N.; Barve, M.; Grisham, R.; Mehr, K.T.; Falk, M.; Beier, F.; Hennessy, M.; Schroeder, A.; et al. Randomized, phase Ib/II study of M6620 + avelumab + carboplatin vs standard care (sc) in patients (pts) with platinum-sensitive poly (ADP-ribose) polymerase inhibitor-(PARPi)-resistant ovarian cancer. Ann. Oncol. 2019, 30, v431–v432. [Google Scholar] [CrossRef]
  201. Shapiro, G.I.; Wesolowski, R.; Devoe, C.; Lord, S.; Pollard, J.; Hendriks, B.S.; Falk, M.; Diaz-Padilla, I.; Plummer, R.; Yap, T.A. Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. Br. J. Cancer 2021, 125, 520–527. [Google Scholar] [CrossRef] [PubMed]
  202. Yap, T.A.; O’Carrigan, B.; Penney, M.S.; Lim, J.S.; Brown, J.S.; Luken, M.J.D.M.; Tunariu, N.; Perez-Lopez, R.; Rodrigues, D.N.; Riisnaes, R.; et al. Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2020, 38, 3195–3204. [Google Scholar] [CrossRef]
  203. Thomas, A.; Takahashi, N.; Rajapakse, V.N.; Zhang, X.; Sun, Y.; Ceribelli, M.; Wilson, K.M.; Zhang, Y.; Beck, E.; Sciuto, L.; et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell 2021, 39, 566–579.e7. [Google Scholar] [CrossRef] [PubMed]
  204. Konstantinopoulos, P.A.; Cheng, S.-C.; Hendrickson, A.E.W.; Penson, R.T.; Schumer, S.T.; Doyle, L.A.; Lee, E.K.; Kohn, E.C.; Duska, L.R.; Crispens, M.A.; et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020, 21, 957–968. [Google Scholar] [CrossRef] [PubMed]
  205. Plummer, E.R.; Kristeleit, R.S.; Cojocaru, E.; Haris, N.M.; Carter, L.; Jones, R.H.; Blagden, S.P.; Evans, T.R.J.; Arkenau, H.-T.; Sarker, D.; et al. A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer. J. Clin. Oncol. 2019, 37, 3094. [Google Scholar] [CrossRef]
  206. Banerji, U.; Plummer, E.R.; Moreno, V.; Ang, J.E.; Quinton, A.; Drew, Y.; Hernández, T.; Roda, D.; Carter, L.; Navarro, A.; et al. A phase I/II first-in-human trial of oral SRA737 (a Chk1 inhibitor) given in combination with low-dose gemcitabine in subjects with advanced cancer. J. Clin. Oncol. 2019, 37, 3095. [Google Scholar] [CrossRef]
  207. Chu, Q.S.; Jonker, D.J.; Provencher, D.M.; Miller, W.H.; Bouganim, N.; Shields, A.F.; Shapiro, G.; Sawyer, M.B.; Lheureux, S.; Samouelian, V.; et al. A phase Ib study of oral Chk1 inhibitor LY2880070 in combination with gemcitabine in patients with advanced or metastatic cancer. J. Clin. Oncol. 2020, 38, 3581. [Google Scholar] [CrossRef]
  208. Konstantinopoulos, P.A.; Lee, J.-M.; Gao, B.; Miller, R.; Lee, J.Y.; Colombo, N.; Vergote, I.; Credille, K.M.; Young, S.R.; McNeely, S.; et al. A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer. Gynecol. Oncol. 2022, 167, 213–225. [Google Scholar] [CrossRef] [PubMed]
  209. Lee, J.M.; Nair, J.; Zimmer, A.; Lipkowitz, S.; Annunziata, C.M.; Merino, M.J.; Swisher, E.M.; Harrell, M.I.; Trepel, J.B.; Lee, M.J.; et al. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: A first-in-class proof-of-concept phase 2 study. Lancet Oncol. 2018, 19, 207–215. [Google Scholar] [CrossRef]
  210. Do, K.T.; Kochupurakkal, B.S.; Kelland, S.; de Jonge, A.; Hedglin, J.; Powers, A.; Quinn, N.; Gannon, C.; Vuong, L.; Parmar, K.; et al. Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors. Clin. Cancer Res. 2021, 27, 4710–4716. [Google Scholar] [CrossRef]
  211. Moore, K.N.; Chambers, S.K.; Hamilton, E.P.; Chen, L.-M.; Oza, A.M.; Ghamande, S.A.; Konecny, G.E.; Plaxe, S.C.; Spitz, D.L.; Geenen, J.J.J.; et al. Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study. Clin. Cancer Res. 2022, 28, 36–44. [Google Scholar] [CrossRef] [PubMed]
  212. Leijen, S.; van Geel, R.M.J.M.; Sonke, G.S.; de Jong, D.; Rosenberg, E.H.; Marchetti, S.; Pluim, D.; van Werkhoven, E.; Rose, S.; Lee, M.A.; et al. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months. J. Clin. Oncol. 2016, 34, 4354–4361. [Google Scholar] [CrossRef] [Green Version]
  213. Lheureux, S.; Cristea, M.C.; Bruce, J.P.; Garg, S.; Cabanero, M.; Mantia-Smaldone, G.; Olawaiye, A.B.; Ellard, S.L.; Weberpals, J.I.; Hendrickson, A.E.W.; et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021, 397, 281–292. [Google Scholar] [CrossRef]
  214. Oza, A.M.; Estevez-Diz, M.D.P.; Grischke, E.-M.; Hall, M.; Marmé, F.; Provencher, D.M.; Uyar, D.S.; Weberpals, J.I.; Wenham, R.M.; Laing, N.; et al. A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer. Clin. Cancer Res. 2020, 26, 4767–4776. [Google Scholar] [CrossRef]
  215. Westin, S.N.; Coleman, R.L.; Fellman, B.M.; Yuan, Y.; Sood, A.K.; Soliman, P.T.; Wright, A.A.; Horowitz, N.S.; Campos, S.M.; Konstantinopoulos, P.A.; et al. EFFORT: EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. J. Clin. Oncol. 2021, 39, 5505. [Google Scholar] [CrossRef]
  216. Hamilton, E.P.; Wang, J.S.-Z.; Falchook, G.; Jones, S.F.; Cook, C.; Mugundu, G.; Jewsbury, P.J.; O’Connor, M.J.; Pierce, A.J.; Li, B.T.; et al. A phase Ib study of AZD1775 and olaparib combination in patients with refractory solid tumors. J. Clin. Oncol. 2016, 34, 5562. [Google Scholar] [CrossRef]
  217. Hamilton, E.; Falchook, G.S.; Wang, J.S.; Fu, S.; Oza, A.; Karen, S.; Imedio, E.R.; Kumar, S.; Ottesen, L.; Mugundu, G.M.; et al. Abstract CT025: Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation. Cancer Res 2019, 79, CT025. [Google Scholar] [CrossRef]
  218. Basu, B.; Gourley, C.; Gabra, H.; Vergote, I.B.; Brenton, J.D.; Abrahmsen, L.; Smith, A.; Von Euler, M.; Green, J.A. PISARRO: A EUTROC phase 1b study of APR-246 with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in relapsed platinum-sensitive high grade serous ovarian cancer (HGSOC). Ann. Oncol. 2016, 27, vi123. [Google Scholar] [CrossRef] [Green Version]
  219. Hanahan, D.; Weinberg, R.A. The Hallmarks of Cancer. Cell 2000, 100, 57–70. [Google Scholar] [CrossRef] [Green Version]
  220. Gerson, S.L. MGMT: Its role in cancer aetiology and cancer therapeutics. Nat. Rev. Cancer 2004, 4, 296–307. [Google Scholar] [CrossRef]
  221. Hegi, M.E.; Diserens, A.-C.; Gorlia, T.; Hamou, M.-F.; De Tribolet, N.; Weller, M.; Kros, J.M.; Hainfellner, J.A.; Mason, W.; Mariani, L.; et al. MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. N. Engl. J. Med. 2005, 352, 997–1003. [Google Scholar] [CrossRef] [Green Version]
  222. Wu, X.; Luo, Q.; Zhao, P.; Chang, W.; Wang, Y.; Shu, T.; Ding, F.; Li, B.; Liu, Z. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proc. Natl. Acad. Sci. USA 2019, 116, 2961–2966. [Google Scholar] [CrossRef] [Green Version]
  223. Toss, A.; Tomasello, C.; Razzaboni, E.; Contu, G.; Grandi, G.; Cagnacci, A.; Schilder, R.J.; Cortesi, L. Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes. BioMed Res. Int. 2015, 2015, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  224. Song, H.; Cicek, M.S.; Dicks, E.; Harrington, P.; Ramus, S.J.; Cunningham, J.M.; Fridley, B.L.; Tyrer, J.P.; Alsop, J.; Jimenez-Linan, M.; et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum. Mol. Genet. 2014, 23, 4703–4709. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Begum, R.; Martin, S.A. Targeting Mismatch Repair defects: A novel strategy for personalized cancer treatment. DNA Repair 2016, 38, 135–139. [Google Scholar] [CrossRef]
  226. Tomasova, K.; Cumova, A.; Seborova, K.; Horák, J.; Koucka, K.; Vodickova, L.; Vaclavikova, R.; Vodicka, P. DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome. Cancers 2020, 12, 1713. [Google Scholar] [CrossRef]
  227. He, Y.; Zhang, L.; Zhou, R.; Wang, Y.; Chen, H. The role of DNA mismatch repair in immunotherapy of human cancer. Int. J. Biol. Sci. 2022, 18, 2821–2832. [Google Scholar] [CrossRef] [PubMed]
  228. Leary, A.; Tan, D.; Ledermann, J. Immune checkpoint inhibitors in ovarian cancer: Where do we stand? Ther. Adv. Med Oncol. 2021, 13, 17588359211039899. [Google Scholar] [CrossRef] [PubMed]
  229. Kelley, M.R.; Fishel, M.L. Overview of DNA repair pathways, current targets, and clinical trials bench to clinic. In DNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications, 2nd ed.; Academic Press: Cambridge, MA, USA, 2016; pp. 1–54. [Google Scholar] [CrossRef]
  230. Topka, S.; Steinsnyder, Z.; Ravichandran, V.; Tkachuk, K.; Kemel, Y.; Bandlamudi, C.; Madsen, M.W.; Furberg, H.; Ouerfelli, O.; Rudin, C.M.; et al. Targeting Germline- and Tumor-Associated Nucleotide Excision Repair Defects in Cancer. Clin. Cancer Res. 2021, 27, 1997–2010. [Google Scholar] [CrossRef]
  231. Ishibashi, M.; Toyoshima, M.; Zhang, X.; Hasegawa-Minato, J.; Shigeta, S.; Usui, T.; Kemp, C.J.; Grandori, C.; Kitatani, K.; Yaegashi, N. Tyrosine kinase receptor TIE-1 mediates platinum resistance by promoting nucleotide excision repair in ovarian cancer. Sci. Rep. 2018, 8, 1–14. [Google Scholar] [CrossRef] [Green Version]
  232. Duan, M.R.; Ulibarri, J.; Liu, K.J.; Mao, P. Role of Nucleotide Excision Repair in Cisplatin Resistance. Int J Mol Sci 2020, 21, 9248. [Google Scholar] [CrossRef]
  233. Gentile, F.; Tuszynski, J.A.; Barakat, K.H. New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy. J. Mol. Graph. Model. 2016, 65, 71–82. [Google Scholar] [CrossRef]
  234. Herrero, A.B.; Martín-Castellanos, C.; Marco, E.; Gago, F.; Moreno, S. Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin. Cancer Res 2006, 66, 8155–8162. [Google Scholar] [CrossRef] [Green Version]
  235. Casado, A.; Callata, H.R.; Manzano, A.; Marquina, G.; Alonso, T.; Gajate, P.; Sotelo, M.; Cabezas, S.; Fernández, C.; Díaz-Rubio, E. Trabectedin for reversing platinum resistance and resensitization to platinum in patients with recurrent ovarian cancer. Future Oncol. 2019, 15, 271–280. [Google Scholar] [CrossRef] [PubMed]
  236. Takahashi, R.; Mabuchi, S.; Kawano, M.; Sasano, T.; Matsumoto, Y.; Kuroda, H.; Kozasa, K.; Hashimoto, K.; Sawada, K.; Kimura, T. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary. PLoS ONE 2016, 11, e0151050. [Google Scholar] [CrossRef]
  237. Kawano, M.; Mabuchi, S.; Kishimoto, T.; Hisamatsu, T.; Matsumoto, Y.; Sasano, T.; Takahashi, R.; Sawada, K.; Takahashi, K.; Takahashi, T.; et al. Combination Treatment With Trabectedin and Irinotecan or Topotecan Has Synergistic Effects Against Ovarian Clear Cell Carcinoma Cells. Int. J. Gynecol. Cancer 2014, 24, 829–837. [Google Scholar] [CrossRef]
  238. Ventriglia, J.; Paciolla, I.; Cecere, S.C.; Pisano, C.; Di Napoli, M.; Arenare, L.; Setola, S.V.; Losito, N.S.; Califano, D.; Orditura, M.; et al. Trabectedin in Ovarian Cancer: Is it now a Standard of Care? Clin. Oncol. 2018, 30, 498–503. [Google Scholar] [CrossRef]
  239. Monk, B.J.; Herzog, T.J.; Kaye, S.B.; Krasner, C.N.; Vermorken, J.B.; Muggia, F.M.; Pujade-Lauraine, E.; Lisyanskaya, A.S.; Makhson, A.N.; Rolski, J.; et al. Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer. J. Clin. Oncol. 2010, 28, 3107–3114. [Google Scholar] [CrossRef]
  240. Monk, B.J.; Dalton, H.; Benjamin, I.; Tanovic, A. Trabectedin as a New Chemotherapy Option in the Treatment of Relapsed Platinum Sensitive Ovarian Cancer. Curr. Pharm. Des. 2012, 18, 3754–3769. [Google Scholar] [CrossRef] [PubMed]
  241. European Medicines Agency. Yondelis. Available online: https://www.ema.europa.eu/en/medicines/human/referrals/yondelis#overview-section (accessed on 17 October 2022).
  242. Vodicka, P.; Urbanova, M.; Makovicky, P.; Tomasova, K.; Kroupa, M.; Stetina, R.; Opattova, A.; Kostovcikova, K.; Siskova, A.; Schneiderova, M.; et al. Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients. Int. J. Mol. Sci. 2020, 21, 2473. [Google Scholar] [CrossRef] [Green Version]
  243. Stoffel, E.M.; Mangu, P.B.; Limburg, P.J. Hereditary Colorectal Cancer Syndromes: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the Familial Risk–Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guidelines. J. Oncol. Pr. 2015, 11, e437–e441. [Google Scholar] [CrossRef] [PubMed]
  244. Wen, X.; Lu, R.; Xie, S.; Zheng, H.; Wang, H.; Wang, Y.; Sun, J.; Gao, X.; Guo, L. APE1 overexpression promotes the progression of ovarian cancer and serves as a potential therapeutic target. Cancer Biomarkers 2016, 17, 313–322. [Google Scholar] [CrossRef]
  245. Zhang, Y.; Wang, J.; Xiang, D.; Wang, D.; Xin, X. Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor. Int. J. Oncol. 2009, 35, 1069–1079. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  246. Zheng, F.; Zhang, Y.; Chen, S.; Weng, X.; Rao, Y.; Fang, H. Mechanism and current progress of Poly ADP-ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer. Biomed. Pharmacother. 2020, 123, 109661. [Google Scholar] [CrossRef] [PubMed]
  247. Patel, M.; Nowsheen, S.; Maraboyina, S.; Xia, F. The role of poly(ADP-ribose) polymerase inhibitors in the treatment of cancer and methods to overcome resistance: A review. Cell Biosci. 2020, 10, 1–12. [Google Scholar] [CrossRef] [PubMed]
  248. Rose, M.; Burgess, J.T.; O’Byrne, K.; Richard, D.J.; Bolderson, E. PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. Front. Cell Dev. Biol. 2020, 8, 879. [Google Scholar] [CrossRef]
  249. Kyo, S.; Kanno, K.; Takakura, M.; Yamashita, H.; Ishikawa, M.; Ishibashi, T.; Sato, S.; Nakayama, K. Clinical Landscape of PARP Inhibitors in Ovarian Cancer: Molecular Mechanisms and Clues to Overcome Resistance. Cancers 2022, 14, 2504. [Google Scholar] [CrossRef]
  250. Miller, R.E.; El-Shakankery, K.H.; Lee, J.Y. PARP inhibitors in ovarian cancer: Overcoming resistance with combination strategies. J. Gynecol. Oncol. 2022, 33, e44. [Google Scholar] [CrossRef] [PubMed]
  251. Kakoti, S.; Sato, H.; Laskar, S.; Yasuhara, T.; Shibata, A. DNA Repair and Signaling in Immune-Related Cancer Therapy. Front. Mol. Biosci. 2020, 7, 205. [Google Scholar] [CrossRef]
  252. Chatterjee, N.; Walker, G.C. Mechanisms of DNA damage, repair, and mutagenesis. Environ. Mol. Mutagen. 2017, 58, 235–263. [Google Scholar] [CrossRef] [Green Version]
  253. Pilié, P.G.; Tang, C.; Mills, G.B.; Yap, T.A. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 2019, 16, 81–104. [Google Scholar] [CrossRef]
  254. Mukhopadhyay, A.; Plummer, E.R.; Elattar, A.; Soohoo, S.; Uzir, B.; Quinn, J.E.; McCluggage, W.G.; Maxwell, P.; Aneke, H.; Curtin, N.J.; et al. Clinicopathological Features of Homologous Recombination–Deficient Epithelial Ovarian Cancers: Sensitivity to PARP Inhibitors, Platinum, and Survival. Cancer Res. 2012, 72, 5675–5682. [Google Scholar] [CrossRef] [Green Version]
  255. Fok, J.H.L.; Ramos-Montoya, A.; Vazquez-Chantada, M.; Wijnhoven, P.W.G.; Follia, V.; James, N.; Farrington, P.M.; Karmokar, A.; Willis, S.E.; Cairns, J.; et al. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat. Commun. 2019, 10, 1–15. [Google Scholar] [CrossRef] [Green Version]
  256. Wise, H.C.; Iyer, G.V.; Moore, K.; Temkin, S.M.; Gordon, S.; Aghajanian, C.; Grisham, R.N. Activity of M3814, an Oral DNA-PK Inhibitor, In Combination with Topoisomerase II Inhibitors in Ovarian Cancer Models. Sci. Rep. 2019, 9, 18882. [Google Scholar] [CrossRef] [Green Version]
  257. Gordhandas, S.B.; Manning-Geist, B.; Henson, C.; Iyer, G.; Gardner, G.J.; Sonoda, Y.; Moore, K.N.; Aghajanian, C.; Chui, M.H.; Grisham, R.N. Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer. Sci. Rep. 2022, 12, 1–6. [Google Scholar] [CrossRef]
  258. Bian, L.; Meng, Y.; Zhang, M.; Li, D. MRE11-RAD50-NBS1 complex alterations and DNA damage response: Implications for cancer treatment. Mol. Cancer 2019, 18, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  259. Herrero, A.B.; San Miguel, J.; Gutierrez, N.C. Deregulation of DNA Double-Strand Break Repair in Multiple Myeloma: Implications for Genome Stability. PLoS ONE 2015, 10, e0121581. [Google Scholar] [CrossRef]
  260. Medova, M.; Medo, M.; Hovhannisyan, L.; Munoz-Maldonado, C.; Aebersold, D.M.; Zimmer, Y. DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions. Pharmacol Therapeut 2020, 215. [Google Scholar] [CrossRef] [PubMed]
  261. ClinicalTrials.Gov. A Study Combining the Peposertib (M3814) Pill with Standard Chemotherapy in Patients with Ovarian Cancer with an Expansion in High Grade Serous Ovarian Cancer and Low Grade Serous Ovarian Cancer. Available online: https://clinicaltrials.gov/ct2/show/NCT04092270 (accessed on 6 October 2022).
  262. Sekiguchi, M.; Matsushita, N. DNA Damage Response Regulation by Histone Ubiquitination. Int. J. Mol. Sci. 2022, 23, 8187. [Google Scholar] [CrossRef]
  263. Mayes, K.; Qiu, Z.; Alhazmi, A.; Landry, J.W. ATP-Dependent Chromatin Remodeling Complexes as Novel Targets for Cancer Therapy. Adv. Cancer Res. 2014, 121, 183–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  264. Klochendler-Yeivin, A.; Picarsky, E.; Yaniv, M. Increased DNA Damage Sensitivity and Apoptosis in Cells Lacking the Snf5/Ini1 Subunit of the SWI/SNF Chromatin Remodeling Complex. Mol. Cell. Biol. 2006, 26, 2661–2674. [Google Scholar] [CrossRef] [Green Version]
  265. Mandal, J.; Mandal, P.; Wang, T.-L.; Shih, I.-M. Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response. J. Biomed. Sci. 2022, 29, 1–15. [Google Scholar] [CrossRef]
  266. Gospodinov, A.; Vaissiere, T.; Krastev, D.B.; Legube, G.; Anachkova, B.; Herceg, Z. Mammalian Ino80 Mediates Double-Strand Break Repair through Its Role in DNA End Strand Resection. Mol. Cell. Biol. 2011, 31, 4735–4745. [Google Scholar] [CrossRef] [Green Version]
  267. Guillemette, S.; Serra, R.W.; Peng, M.; Hayes, J.A.; Konstantinopoulos, P.A.; Green, M.R.; Cantor, S.B. Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. Genes Dev. 2015, 29, 489–494. [Google Scholar] [CrossRef]
  268. Li, Y.; Gong, H.; Wang, P.; Zhu, Y.; Peng, H.; Cui, Y.; Li, H.; Liu, J.; Wang, Z. The emerging role of ISWI chromatin remodeling complexes in cancer. J. Exp. Clin. Cancer Res. 2021, 40, 1–27. [Google Scholar] [CrossRef]
  269. Hall, M.J.; Bernhisel, R.; Hughes, E.; Larson, K.; Rosenthal, E.T.; Singh, N.A.; Lancaster, J.M.; Kurian, A.W. Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers. Cancer Prev. Res. 2021, 14, 433–440. [Google Scholar] [CrossRef]
  270. Sugino, K.; Tamura, R.; Nakaoka, H.; Yachida, N.; Yamaguchi, M.; Mori, Y.; Yamawaki, K.; Suda, K.; Ishiguro, T.; Adachi, S.; et al. Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients. Sci. Rep. 2019, 9, 1–9. [Google Scholar] [CrossRef] [Green Version]
  271. Llorens-Agost, M.; Luessing, J.; van Beneden, A.; Eykelenboom, J.; O’Reilly, D.; Bicknell, L.S.; Reynolds, J.J.; van Koegelenberg, M.; Hurles, M.E.; Brady, A.F.; et al. Analysis of novel missense ATR mutations reveals new splicing defects underlying Seckel syndrome. Hum. Mutat. 2018, 39, 1847–1853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  272. Stolarova, L.; Kleiblova, P.; Janatova, M.; Soukupova, J.; Zemankova, P.; Macurek, L.; Kleibl, Z. CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells 2020, 9, 2675. [Google Scholar] [CrossRef] [PubMed]
  273. Gillespie, D.A. When more is less: Heritable gain-of-function chk1 mutations impair human fertility. FEBS J. 2022, in press. [Google Scholar] [CrossRef] [PubMed]
  274. Ronco, C.; Martin, A.R.; Demange, L.; Benhida, R. ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells. MedChemComm 2016, 8, 295–319. [Google Scholar] [CrossRef]
  275. Chen, C.-W.; Buj, R.; Dahl, E.S.; Leon, K.E.; Aird, K.M. ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells. Heliyon 2020, 6, e05097. [Google Scholar] [CrossRef]
  276. Biegala, L.; Gajek, A.; Marczak, A.; Rogalska, A. Olaparib in Combination with Inhibitors of Atr/Chk1 Pathway Leads to Increased Cell Death in Ovarian Cancer Cells Sensitive and Resistant to Parpi. Int J Gynecol Cancer 2021, 31, A375–A376. [Google Scholar] [CrossRef]
  277. Barnieh, F.M.; Loadman, P.M.; Falconer, R.A. Progress towards a clinically-successful ATR inhibitor for cancer therapy. Curr. Res. Pharmacol. Drug Discov. 2021, 2, 100017. [Google Scholar] [CrossRef]
  278. Sultana, R.; Abdel-Fatah, T.; Perry, C.; Moseley, P.; Albarakti, N.; Mohan, V.; Seedhouse, C.; Chan, S.; Madhusudan, S. Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase Inhibition Is Synthetically Lethal in XRCC1 Deficient Ovarian Cancer Cells. Plos One 2013, 8. [Google Scholar] [CrossRef] [Green Version]
  279. Gralewska, P.; Gajek, A.; Rybaczek, D.; Marczak, A.; Rogalska, A. The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCA(MUT) and BRCA(WT) Ovarian Cancer Cells. Cells-Basel 2022, 11, 1889. [Google Scholar] [CrossRef]
  280. Yap, T.A.; Tan, D.S.; Stathis, A.; Shapiro, G.I.; Iwasa, S.; Joerger, M.; Zhang, J.; Plummer, R.; Sawyer, M.; Tan, A.C.; et al. Abstract CT006: Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects. Cancer Res 2022, 82, CT006. [Google Scholar] [CrossRef]
  281. Konstantinopoulos, P.A.; da Costa, A.A.B.A.; Gulhan, D.; Lee, E.K.; Cheng, S.-C.; Hendrickson, A.E.W.; Kochupurakkal, B.; Kolin, D.L.; Kohn, E.C.; Liu, J.F.; et al. A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer. Nat. Commun. 2021, 12, 1–8. [Google Scholar] [CrossRef]
  282. Serda, M.; Becker, F.G.; Cleary, M.; Team, R.M.; Holtermann, H.; The, D.; Agenda, N.; Science, P.; Sk, S.K.; Hinnebusch, R.; et al. SRA737, a Novel Chk1 Inhibitor, Shows Efficacy in CCNE1-Amplified and MYCN-Overexpressing High-Grade Serous Ovarian Cancer Patient-Derived Xenograft Models. Eur. J. Cancer 2018, 103, e98. [Google Scholar]
  283. Park, S.J.; Chang, S.J.; Suh, D.H.; Kong, T.W.; Song, H.; Kim, T.H.; Kim, J.W.; Kim, H.S.; Lee, S.J. A Phase IA Dose-Escalation Study of PHI-101, a New Checkpoint Kinase 2 Inhibitor, for Platinum-Resistant Recurrent Ovarian Cancer. BMC Cancer 2022, 22, 1–7. [Google Scholar] [CrossRef] [PubMed]
  284. Nair, J.; Huang, T.T.; Murai, J.; Haynes, B.; Steeg, P.S.; Pommier, Y.; Lee, J.M. Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer. Oncogene 2020, 39, 5520–5535. [Google Scholar] [CrossRef]
  285. Lampert, E.J.; An, D.; McCoy, A.; Kohn, E.C.; Annunziata, C.M.; Trewhitt, K.; Zimmer, A.D.S.; Lipkowitz, S.; Lee, J.-M. Prexasertib, a cell cycle checkpoint kinase 1 inhibitor, in BRCA mutant recurrent high-grade serous ovarian cancer (HGSOC): A proof-of-concept single arm phase II study. J. Clin. Oncol. 2020, 38, 6038. [Google Scholar] [CrossRef]
  286. Zhang, M.; Dominguez, D.; Chen, S.; Fan, J.; Qin, L.; Long, A.; Li, X.; Zhang, Y.; Shi, H.; Zhang, B. WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. Oncol. Lett. 2017, 14, 3580–3586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  287. De Witte, C.J.; Valle-Inclan, J.E.; Hami, N.; Lõhmussaar, K.; Kopper, O.; Vreuls, C.P.H.; Jonges, G.N.; van Diest, P.; Nguyen, L.; Clevers, H.; et al. Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses. Cell Rep. 2019, 31, 107762. [Google Scholar] [CrossRef]
  288. Zilfou, J.T.; Lowe, S.W. Tumor Suppressive Functions of p53. Cold Spring Harb. Perspect. Biol. 2009, 1, a001883. [Google Scholar] [CrossRef]
  289. Brown, C.J.; Cheok, C.F.; Verma, C.S.; Lane, D.P. Reactivation of p53: From peptides to small molecules. Trends Pharmacol. Sci. 2011, 32, 53–62. [Google Scholar] [CrossRef]
  290. Selivanova, G.; Wiman, K.G. Reactivation of mutant p53: Molecular mechanisms and therapeutic potential. Oncogene 2007, 26, 2243–2254. [Google Scholar] [CrossRef] [Green Version]
  291. Yoshikawa, N.; Kajiyama, H.; Nakamura, K.; Utsumi, F.; Niimi, K.; Mitsui, H.; Sekiya, R.; Suzuki, S.; Shibata, K.; Callen, D.; et al. PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells. Oncol. Rep. 2016, 35, 2543–2552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  292. Vassilev, L.T.; Vu, B.T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303, 844–848. [Google Scholar] [CrossRef] [Green Version]
  293. Carrillo, A.M.; Hicks, M.; Khabele, D.; Eischen, C.M. Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells. Mol. Cancer Res. 2015, 13, 1197–1205. [Google Scholar] [CrossRef] [PubMed]
  294. Vanderstichele, A.; Loverix, L.; Busschaert, P.; van Nieuwenhuysen, E.; Han, S.N.; Concin, N.; Callewaert, T.; Olbrecht, S.; Salihi, R.; Berteloot, P.; et al. Randomized CLIO/BGOG-Ov10 Trial of Olaparib Monotherapy versus Physician’s Choice Chemotherapy in Relapsed Ovarian Cancer. Gynecol. Oncol. 2022, 165, 14–22. [Google Scholar] [CrossRef] [PubMed]
  295. Gelmon, K.A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; et al. Olaparib in Patients with Recurrent High-Grade Serous or Poorly Differentiated Ovarian Carcinoma or Triple-Negative Breast Cancer: A Phase 2, Multicentre, Open-Label, Non-Randomised Study. Lancet Oncol. 2011, 12, 852–861. [Google Scholar] [CrossRef]
  296. Domchek, S.M.; Aghajanian, C.; Shapira-Frommer, R.; Schmutzler, R.K.; Audeh, M.W.; Friedlander, M.; Balmaña, J.; Mitchell, G.; Fried, G.; Stemmer, S.M.; et al. Efficacy and Safety of Olaparib Monotherapy in Germline BRCA1/2 Mutation Carriers with Advanced Ovarian Cancer and Three or More Lines of Prior Therapy. Gynecol. Oncol. 2016, 140, 199–203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  297. Audeh, M.W.; Carmichael, J.; Penson, R.T.; Friedlander, M.; Powell, B.; Bell-McGuinn, K.M.; Scott, C.; Weitzel, J.N.; Oaknin, A.; Loman, N.; et al. Oral Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Patients with BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer: A Proof-of-Concept Trial. Lancet 2010, 376, 245–251. [Google Scholar] [CrossRef] [PubMed]
  298. Cadoo, K.A.; Simpkins, F.; Mathews, C.A.; Kabil, N.; Bennett, J.; Aghajanian, C. Olaparib Treatment in Patients (Pts) with Platinum-Sensitive Relapsed (PSR) Ovarian Cancer (OC) by BRCA Mutation (BRCAm) and Homologous Recombination Deficiency (HRD) Status: Phase II LIGHT Study. J. Clin. Oncol. 2020, 38, 6013. [Google Scholar] [CrossRef]
  299. Ledermann, J.A.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Overall Survival in Patients with Platinum-Sensitive Recurrent Serous Ovarian Cancer Receiving Olaparib Maintenance Monotherapy: An Updated Analysis from a Randomised, Placebo-Controlled, Double-Blind, Phase 2 Trial. Lancet Oncol. 2016, 17, 1579–1589. [Google Scholar] [CrossRef]
  300. Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N. Engl. J. Med. 2012, 366, 1382–1392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  301. DiSilvestro, P.; Banerjee, S.; Colombo, N.; Scambia, G.; Kim, B.-G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; et al. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial. J. Clin. Oncol. 2022. [Google Scholar] [CrossRef]
  302. Banerjee, S.; Moore, K.N.; Colombo, N.; Scambia, G.; Kim, B.G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; et al. Maintenance Olaparib for Patients with Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation (SOLO1/GOG 3004): 5-Year Follow-up of a Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2021, 22, 1721–1731. [Google Scholar] [CrossRef]
  303. Friedlander, M.; Moore, K.N.; Colombo, N.; Scambia, G.; Kim, B.G.; Oaknin, A.; Lisyanskaya, A.; Sonke, G.S.; Gourley, C.; Banerjee, S.; et al. Patient-Centred Outcomes and Effect of Disease Progression on Health Status in Patients with Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation Receiving Maintenance Olaparib or Placebo (SOLO1): A Randomised, Phase 3 Trial. Lancet Oncol. 2021, 22, 632–642. [Google Scholar] [CrossRef]
  304. Moore, K.; Colombo, N.; Scambia, G.; Kim, B.-G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; Sonke, G.S.; et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2018, 379, 2495–2505. [Google Scholar] [CrossRef]
  305. Penson, R.T.; Valencia, R.V.; Cibula, D.; Colombo, N.; Leath, C.A.; Bidzinski, M.; Kim, J.W.; Nam, J.H.; Madry, R.; Hernández, C.; et al. Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. J. Clin. Oncol. 2020, 38, 1164–1174. [Google Scholar] [CrossRef]
  306. Pujade-Lauraine, E.; Ledermann, J.A.; Selle, F.; Gebski, V.; Penson, R.T.; Oza, A.M.; Korach, J.; Huzarski, T.; Poveda, A.; Pignata, S.; et al. Olaparib Tablets as Maintenance Therapy in Patients with Platinum-Sensitive, Relapsed Ovarian Cancer and a BRCA1/2 Mutation (SOLO2/ENGOT-Ov21): A Double-Blind, Randomised, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2017, 18, 1274–1284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  307. Poveda, A.; Lheureux, S.; Colombo, N.; Cibula, D.; Lindemann, K.; Weberpals, J.; Bjurberg, M.; Oaknin, A.; Sikorska, M.; González-Martín, A.; et al. Olaparib Maintenance Monotherapy in Platinum-Sensitive Relapsed Ovarian Cancer Patients without a Germline BRCA1/BRCA2 Mutation: OPINION Primary Analysis. Gynecol. Oncol. 2022, 164, 498–504. [Google Scholar] [CrossRef]
  308. Gao, Q.; Zhu, J.; Zhao, W.; Huang, Y.; An, R.; Zheng, H.; Qu, P.; Wang, L.; Zhou, Q.; Wang, D.; et al. L-MOCA: An Open-Label Study of Olaparib Maintenance Monotherapy in Platinum-Sensitive Relapsed Ovarian Cancer. J. Clin. Oncol. 2021, 39, e17526. [Google Scholar] [CrossRef]
  309. Pujade-Lauraine, E.; Selle, F.; Scambia, G.; Asselain, B.; Marmé, F.; Lindemann, K.; Colombo, N.; Madry, R.; Glasspool, R.M.; Dubot, C.; et al. LBA33 Maintenance Olaparib Rechallenge in Patients (Pts) with Ovarian Carcinoma (OC) Previously Treated with a PARP Inhibitor (PARPi): Phase IIIb OReO/ENGOT Ov-38 Trial. Ann. Oncol. 2021, 32, S1308–S1309. [Google Scholar] [CrossRef]
  310. Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer. Available online: https://clin.larvol.com/trial-detail/NCT04330040/261112 (accessed on 27 November 2022).
  311. Pignata, S.; Oza, A.; Hall, G.; Pardo, B.; Madry, R.; Cibula, D.; Klat, J.; Montes, A.; Glasspool, R.; Colombo, N.; et al. ORZORA: Maintenance Olaparib in Patients with Platinum-Sensitive Relapsed Ovarian Cancer: Outcomes by Somatic and Germline BRCA and Other Homologous Recombination Repair Gene Mutation Status. Gynecol. Oncol. 2021, 162, S29. [Google Scholar] [CrossRef]
  312. Marme, F.; Hilpert, F.; Welslau, M.; El-Balat, A.; Grischke, E.-M.; Schinkothe, T.; Glowik, R.; Sehouli, J. Olaparib in German Routine Clinical Practice: Updated Interim Results of the Non-Interventional Study C-PATROL. J. Clin. Oncol. 2018, 36, e17549. [Google Scholar] [CrossRef]
  313. de La Motte Rouge, T.; Bengrine Lefevre, L.; Mouret-Reynier, M.-A.; Asselain, B.; Lucas, B.; Gavoille, C.; Cornila, C.; Spaeth, D.; Colomba, E.; Patsouris, A.; et al. 823P Extended Follow-up of a Real-World Cohort of Patients (Pts) with BRCA Mutation (BRCAm) Relapsed Epithelial Ovarian Cancer (EOC) Receiving Olaparib Maintenance Therapy: The GINECO RETROLA Study. Ann. Oncol. 2020, 31, S621–S622. [Google Scholar] [CrossRef]
  314. Lorusso, D.; Gourley, C.; Garbay, D.; Jean, B.; Asselain, R.; Raspagliesi, F.; Zamagni, C.; Leary, A.; Bellier, C.; Glasspool, R.; et al. 2022-RA-944-ESGO Real-World Safety, Baseline Characteristics and First-Year Therapy Management in Patients with BRCA1/BRCA2-Mutated Advanced Ovarian Cancer Treated with Olaparib Tablets in the First-Line Maintenance Setting: First Analysis of the Pan-European OVAL-1 Study. Int J Gynecol Cancer 2022, 32. [Google Scholar] [CrossRef]
  315. Konner, J.A.; Boucicaut, N.N.; O’Cearbhaill, R.E.; Zamarin, D.; Makker, V.; Sabbatini, P.; Tew, W.P.; Cadoo, K.A.; Grisham, R.N.; Aghajanian, C. A Phase I Dose-Escalation Study of Intraperitoneal (IP) Cisplatin, IV/IP Paclitaxel, IV Bevacizumab, and Oral Olaparib for Newly Diagnosed Adenxal Carcinoma. J. Clin. Oncol. 2017, 35, 5572. [Google Scholar] [CrossRef]
  316. Rivkin, S.E.; Moon, J.; Iriarte, D.S.; Bailey, E.; Sloan, H.L.; Goodman, G.E.; Bondurant, A.E.; Velijovich, D.; Wahl, T.; Jiang, P.; et al. Phase Ib with Expansion Study of Olaparib plus Weekly (Metronomic) Carboplatin and Paclitaxel in Relapsed Ovarian Cancer Patients. Int J Gynecol Cancer 2019, 29, 325–333. [Google Scholar] [CrossRef]
  317. Oza, A.M.; Cibula, D.; Benzaquen, A.O.; Poole, C.; Mathijssen, R.H.J.; Sonke, G.S.; Colombo, N.; Špaček, J.; Vuylsteke, P.; Hirte, H.; et al. Olaparib Combined with Chemotherapy for Recurrent Platinum-Sensitive Ovarian Cancer: A Randomised Phase 2 Trial. Lancet Oncol. 2015, 16, 87–97. [Google Scholar] [CrossRef]
  318. Kaye, S.B.; Lubinski, J.; Matulonis, U.; Ang, J.E.; Gourley, C.; Karlan, B.Y.; Amnon, A.; Bell-McGuinn, K.M.; Chen, L.M.; Friedlander, M.; et al. Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients with BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer. J. Clin. Oncol. 2012, 30, 372–379. [Google Scholar] [CrossRef]
  319. Harter, P.; Mouret-Reynier, M.A.; Pignata, S.; Cropet, C.; González-Martín, A.; Bogner, G.; Fujiwara, K.; Vergote, I.; Colombo, N.; Nøttrup, T.J.; et al. Efficacy of Maintenance Olaparib plus Bevacizumab According to Clinical Risk in Patients with Newly Diagnosed, Advanced Ovarian Cancer in the Phase III PAOLA-1/ENGOT-Ov25 Trial. Gynecol. Oncol. 2022, 164, 254–264. [Google Scholar] [CrossRef] [PubMed]
  320. Ray-Coquard, I.; Pautier, P.; Pignata, S.; Pérol, D.; González-Martín, A.; Berger, R.; Fujiwara, K.; Vergote, I.; Colombo, N.; Mäenpää, J.; et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2416–2428. [Google Scholar] [CrossRef]
  321. González-Martín, A.; Desauw, C.; Heitz, F.; Cropet, C.; Gargiulo, P.; Berger, R.; Ochi, H.; Vergote, I.; Colombo, N.; Mirza, M.R.; et al. Maintenance Olaparib plus Bevacizumab in Patients with Newly Diagnosed Advanced High-Grade Ovarian Cancer: Main Analysis of Second Progression-Free Survival in the Phase III PAOLA-1/ENGOT-Ov25 Trial. Eur J Cancer 2022, 174, 221–231. [Google Scholar] [CrossRef]
  322. Ray-Coquard, I.L.; Pautier, P.; Pignata, S.; Pérol, D.; González-Martín, A.; Sevelda, P.; Fujiwara, K.; Vergote, I.B.; Colombo, N.; Mäenpää, J.; et al. Phase III PAOLA-1/ENGOT-Ov25 Trial: Olaparib plus Bevacizumab (Bev) as Maintenance Therapy in Patients (Pts) with Newly Diagnosed, Advanced Ovarian Cancer (OC) Treated with Platinum-Based Chemotherapy (PCh) plus Bev. Ann. Oncol. 2019, 30, v894–v895. [Google Scholar] [CrossRef]
  323. LEE, J.-Y.; Kim, J.-W.; Kim, B.-G.; Kim, S.W.; Kim, H.S.; Kim, S.I.; Lim, M.C.; Choi, C.H.; Ngoi, N.; Tan, D.S.P.; et al. Interim Analysis from a Phase II Study of Olaparib Maintenance with Pembrolizumab and Bevacizumab in BRCA Non-Mutated Patients with Platinum-Sensitive Recurrent Ovarian Cancer: APGOT-Ov4/ OPEB-01. J. Clin. Oncol. 2022, 40, e17579. [Google Scholar] [CrossRef]
  324. Peer, C.J.; Lee, J.M.; Roth, J.; Rodgers, L.; Nguyen, J.; Annunziata, C.M.; Minasian, L.; Kohn, E.C.; Figg, W.D. Population Pharmacokinetic Analyses of the Effect of Carboplatin Pretreatment on Olaparib in Recurrent or Refractory Women’s Cancers. Cancer Chemother. Pharmacol. 2017, 80, 165. [Google Scholar] [CrossRef] [PubMed]
  325. Lee, J.M.; Hays, J.L.; Annunziata, C.M.; Noonan, A.M.; Minasian, L.; Zujewski, J.A.; Yu, M.; Gordon, N.; Ji, J.; Sissung, T.M.; et al. Phase I/Ib Study of Olaparib and Carboplatin in BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses. J. Natl. Cancer Inst. 2014, 106. [Google Scholar] [CrossRef]
  326. Geenen, J.J.J.; Dackus, G.M.H.E.; Schouten, P.C.; Pluim, D.; Marchetti, S.; Sonke, G.S.; Jóźwiak, K.; Huitema, A.D.R.; Beijnen, J.H.; Schellens, J.H.M.; et al. A Phase I Dose-escalation Study of Two Cycles Carboplatin-olaparib Followed by Olaparib Monotherapy in Patients with Advanced Cancer. Int. J. Cancer 2021, 148, 3041. [Google Scholar] [CrossRef] [PubMed]
  327. Liu, J.F.; Barry, W.T.; Birrer, M.; Lee, J.M.; Buckanovich, R.J.; Fleming, G.F.; Rimel, B.J.; Buss, M.K.; Nattam, S.R.; Hurteau, J.; et al. Overall Survival and Updated Progression-Free Survival Outcomes in a Randomized Phase II Study of Combination Cediranib and Olaparib versus Olaparib in Relapsed Platinum-Sensitive Ovarian Cancer. Ann. Oncol. 2019, 30, 551–557. [Google Scholar] [CrossRef] [PubMed]
  328. Liu, J.F.; Barry, W.T.; Birrer, M.; Lee, J.M.; Buckanovich, R.J.; Fleming, G.F.; Rimel, B.J.; Buss, M.K.; Nattam, S.; Hurteau, J.; et al. A Randomized Phase 2 Study of Combination Cediranib and Olaparib versus Olaparib Alone as Recurrence Therapy in Platinum-Sensitive Ovarian Cancer. Lancet Oncol. 2014, 15, 1207. [Google Scholar] [CrossRef] [Green Version]
  329. Colombo, N.; Tomao, F.; Benedetti Panici, P.; Nicoletto, M.O.; Tognon, G.; Bologna, A.; Lissoni, A.A.; DeCensi, A.; Lapresa, M.; Mancari, R.; et al. Randomized Phase II Trial of Weekly Paclitaxel vs. Cediranib-Olaparib (Continuous or Intermittent Schedule) in Platinum-Resistant High-Grade Epithelial Ovarian Cancer. Gynecol. Oncol. 2022, 164, 505–513. [Google Scholar] [CrossRef] [PubMed]
  330. Lheureux, S.; Oaknin, A.; Garg, S.; Bruce, J.P.; Madariaga, A.; Dhani, N.C.; Bowering, V.; White, J.; Accardi, S.; Tan, Q.; et al. EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. Clin. Cancer Res. 2020, 26, 4206–4215. [Google Scholar] [CrossRef] [PubMed]
  331. Lee, J.M.; Moore, R.G.; Ghamande, S.; Park, M.S.; Diaz, J.P.; Chapman, J.; Kendrick, J.; Slomovitz, B.M.; Tewari, K.S.; Lowe, E.S.; et al. Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. Clin. Cancer Res. 2022, 28, 4186–4193. [Google Scholar] [CrossRef]
  332. Nicum, S.; Holmes, J.; McGregor, N.; Dunn, R.; Collins, L.; Kaye, S.; McNeish, I.; Glasspool, R.M.; Hall, M.; Roux, R.; et al. 722O Randomised Phase II Trial of Olaparib Compared to Weekly Paclitaxel or Olaparib plus Cediranib in Patients with Platinum-Resistant Ovarian Cancer (OCTOVA). Ann. Oncol. 2021, 32, S725–S726. [Google Scholar] [CrossRef]
  333. Liu, J.F.; Brady, M.F.; Matulonis, U.A.; Miller, A.; Kohn, E.C.; Swisher, E.M.; Tew, W.P.; Cloven, N.G.; Muller, C.; Bender, D.; et al. A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer. J. Clin. Oncol. 2020, 38, 6003. [Google Scholar] [CrossRef]
  334. Liu, J.F.; Brady, M.F.; Matulonis, U.A.; Miller, A.; Kohn, E.C.; Swisher, E.M.; Cella, D.; Tew, W.P.; Cloven, N.G.; Muller, C.Y.; et al. Olaparib With or Without Cediranib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer (NRG-GY004): A Randomized, Open-Label, Phase III Trial. J. Clin. Oncol. 2022, 40, 2138–2147. [Google Scholar] [CrossRef]
  335. Kurnit, K.C.; Meric-Bernstam, F.; Hess, K.; Coleman, R.L.; Bhosale, P.; Savelieva, K.; Janku, F.; Hong, D.; Naing, A.; Pant, S.; et al. Abstract CT020: Phase I Dose Escalation of Olaparib (PARP Inhibitor) and Selumetinib (MEK Inhibitor) Combination in Solid Tumors with Ras Pathway Alterations. Cancer Res 2019, 79, CT020. [Google Scholar] [CrossRef]
  336. Matulonis, U.A.; Wulf, G.M.; Barry, W.T.; Birrer, M.; Westin, S.N.; Farooq, S.; Bell-McGuinn, K.M.; Obermayer, E.; Whalen, C.; Spagnoletti, T.; et al. Phase I Dose Escalation Study of the PI3kinase Pathway Inhibitor BKM120 and the Oral Poly (ADP Ribose) Polymerase (PARP) Inhibitor Olaparib for the Treatment of High-Grade Serous Ovarian and Breast Cancer. Ann. Oncol. 2017, 28, 512–518. [Google Scholar] [CrossRef] [PubMed]
  337. Phase II Study of Olaparib plus Durvalumab with or without Bevacizumab (MEDIOLA): Final Analysis of Overall Survival in Patients with Non-Germline... | OncologyPRO. Available online: https://oncologypro.esmo.org/meeting-resources/esmo-congress/phase-ii-study-of-olaparib-plus-durvalumab-with-or-without-bevacizumab-mediola-final-analysis-of-overall-survival-in-patients-with-non-germline (accessed on 28 November 2022).
  338. Adams, S.F.; Rixe, O.; Lee, J.-H.; McCance, D.J.; Westgate, S.; Eberhardt, S.C.; Rutledge, T.; Muller, C. Phase I Study Combining Olaparib and Tremelimumab for the Treatment of Women with BRCA-Deficient Recurrent Ovarian Cancer. J. Clin. Oncol. 2017, 35, e17052. [Google Scholar] [CrossRef]
  339. Zhang, J.; Zheng, H.; Gao, Y.; Lou, G.; Yin, R.; Ji, D.; Li, W.; Wang, W.; Xia, B.; Wang, D.; et al. Phase I Pharmacokinetic Study of Niraparib in Chinese Patients with Epithelial Ovarian Cancer. Oncologist 2020, 25, 19. [Google Scholar] [CrossRef] [Green Version]
  340. Akce, M.; El-Khoueiry, A.; Piha-Paul, S.A.; Bacque, E.; Pan, P.; Zhang, Z.Y.; Ewesuedo, R.; Gupta, D.; Tang, Y.; Milton, A.; et al. Pharmacokinetics and Safety of Niraparib in Patients with Moderate Hepatic Impairment. Cancer Chemother. Pharmacol. 2021, 88, 825–836. [Google Scholar] [CrossRef]
  341. Moore, K.N.; Secord, A.A.; Geller, M.A.; Miller, D.S.; Cloven, N.; Fleming, G.F.; Wahner Hendrickson, A.E.; Azodi, M.; DiSilvestro, P.; Oza, A.M.; et al. Niraparib Monotherapy for Late-Line Treatment of Ovarian Cancer (QUADRA): A Multicentre, Open-Label, Single-Arm, Phase 2 Trial. Lancet Oncol. 2019, 20, 636–648. [Google Scholar] [CrossRef] [PubMed]
  342. Yu, Y.; Zhang, W.; Liu, R.; Shan, W.; Li, H.; Liu, J.; Xia, B.; He, S.; Xia, Y.; Wang, S.; et al. Effectiveness and Safety of Niraparib as Neoadjuvant Therapy in Advanced Ovarian Cancer with Homologous Recombination Deficiency: NANT Study Protocol for a Prospective, Multicenter, Exploratory, Phase 2, Single-Arm Study (041). Gynecol. Oncol. 2022, 166, S28–S29. [Google Scholar] [CrossRef]
  343. Takehara, K.; Matsumoto, T.; Hamanishi, J.; Hasegawa, K.; Matsuura, M.; Miura, K.; Nagao, S.; Nakai, H.; Tanaka, N.; Tokunaga, H.; et al. Phase 2 Single-Arm Study on the Safety of Maintenance Niraparib in Japanese Patients with Platinum-Sensitive Relapsed Ovarian Cancer. J. Gynecol. Oncol. 2021, 32, 1–11. [Google Scholar] [CrossRef] [PubMed]
  344. Okamoto, A.; Kondo, E.; Nakamura, T.; Yanagida, S.; Hamanishi, J.; Harano, K.; Hasegawa, K.; Hirasawa, T.; Hori, K.; Komiyama, S.; et al. Phase 2 Single-Arm Study on the Efficacy and Safety of Niraparib in Japanese Patients with Heavily Pretreated, Homologous Recombination-Deficient Ovarian Cancer. J. Gynecol. Oncol. 2021, 32, 1–12. [Google Scholar] [CrossRef]
  345. Yin, R.; Li, N.; Wu, L.; Wang, J.; Zhu, J.; Pan, L.; Kong, B.; Zheng, H.; Liu, J.; Wu, X.; et al. Efficacy of Niraparib Maintenance Therapy in Patients with Newly Diagnosed Advanced Ovarian Cancer in Phase 3 PRIME Study: A Subgroup Analysis by Response to First-Line Platinum-Based Chemotherapy. J. Clin. Oncol. 2022, 40, 5551. [Google Scholar] [CrossRef]
  346. O’Cearbhaill, R.E.; Pérez-Fidalgo, J.A.; Monk, B.J.; Tusquets, I.; McCormick, C.; Fuentes, J.; Moore, R.G.; Vulsteke, C.; Shahin, M.S.; Forget, F.; et al. Efficacy of Niraparib by Time of Surgery and Postoperative Residual Disease Status: A Post Hoc Analysis of Patients in the PRIMA/ENGOT-OV26/GOG-3012 Study. Gynecol. Oncol. 2022, 166, 36–43. [Google Scholar] [CrossRef]
  347. del Campo, J.M.; Matulonis, U.A.; Malander, S.; Provencher, D.; Mahner, S.; Follana, P.; Waters, J.; Berek, J.S.; Woie, K.; Oza, A.M.; et al. Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial. J. Clin. Oncol. 2019, 37, 2968–2973. [Google Scholar] [CrossRef]
  348. Matulonis, U.A.; Walder, L.; Nøttrup, T.J.; Bessette, P.; Mahner, S.; Gil-Martin, M.; Kalbacher, E.; Ledermann, J.A.; Wenham, R.M.; Woie, K.; et al. Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial. J. Clin. Oncol. 2019, 37, 3183–3191. [Google Scholar] [CrossRef]
  349. Vilming, B.; Dahl, J.F.; Aune, G.; Zucknick, M.; Lindemann, K. Real-Life Use of Niraparib in a Patient Access Program in Norway. 2021. Available online: https://hdl.handle.net/11250/2775965 (accessed on 31 October 2022).
  350. Liu, G.; Feng, Y.; Li, J.; Deng, T.; Yin, A.; Yan, L.; Zheng, M.; Xiong, Y.; Li, J.; Huang, Y.; et al. A Novel Combination of Niraparib and Anlotinib in Platinum-Resistant Ovarian Cancer: Efficacy and Safety Results from the Phase II, Multi-Center ANNIE Study. EClinicalMedicine 2022, 0, 101767. [Google Scholar] [CrossRef]
  351. Mirza, M.R.; Nyvang, G.-B.; Lund, B.; Christensen, R.d.; Werner, T.L.; Malander, S.; Bjørge, L.; Birrer, M.J.; Anttila, M.; Lindahl, G.; et al. Final Survival Analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of Niraparib and Bevacizumab versus Niraparib Alone as Treatment of Recurrent Platinum-Sensitive Ovarian Cancer—A Randomized Controlled Chemotherapy-Free Study. J. Clin. Oncol. 2020, 38, 6012. [Google Scholar] [CrossRef]
  352. Mirza, M.R.; Åvall Lundqvist, E.; Birrer, M.J.; dePont Christensen, R.; Nyvang, G.B.; Malander, S.; Anttila, M.; Werner, T.L.; Lund, B.; Lindahl, G.; et al. Niraparib plus Bevacizumab versus Niraparib Alone for Platinum-Sensitive Recurrent Ovarian Cancer (NSGO-AVANOVA2/ENGOT-Ov24): A Randomised, Phase 2, Superiority Trial. Lancet Oncol. 2019, 20, 1409–1419. [Google Scholar] [CrossRef] [PubMed]
  353. Mirza, M.R.; Bergmann, T.K.; Mau-Sørensen, M.; Christensen, R. de P.; Åvall-Lundqvist, E.; Birrer, M.J.; Jørgensen, M.; Roed, H.; Malander, S.; Nielsen, F.; et al. A Phase I Study of the PARP Inhibitor Niraparib in Combination with Bevacizumab in Platinum-Sensitive Epithelial Ovarian Cancer: NSGO AVANOVA1/ENGOT-OV24. Cancer Chemother. Pharmacol. 2019, 84, 791–798. [Google Scholar] [CrossRef]
  354. Hardesty, M.M.; Krivak, T.C.; Wright, G.S.; Hamilton, E.; Fleming, E.L.; Belotte, J.; Keeton, E.K.; Wang, P.; Gupta, D.; Clements, A.; et al. OVARIO Phase II Trial of Combination Niraparib plus Bevacizumab Maintenance Therapy in Advanced Ovarian Cancer Following First-Line Platinum-Based Chemotherapy with Bevacizumab. Gynecol. Oncol. 2022, 166, 219–229. [Google Scholar] [CrossRef] [PubMed]
  355. Liu, J.; Gaillard, S.; Hendrickson, A.W.; Moroney, J.; Yeku, O.; Diver, E.; Gunderson, C.; Arend, R.; Ratner, E.; Samnotra, V.; et al. An Open-Label Phase II Study of Dostarlimab (TSR-042), Bevacizumab (Bev), and Niraparib Combination in Patients (Pts) with Platinum-Resistant Ovarian Cancer (PROC): Cohort A of the OPAL Trial. Gynecol. Oncol. 2021, 162, S17–S18. [Google Scholar] [CrossRef]
  356. Randall, L.M.; O’Malley, D.M.; Monk, B.J.; Coleman, R.L.; Gaillard, S.; Adams, S.F.; Duska, L.R.; Cappuccini, F.; Dalton, H.; Holloway, R.W.; et al. MOONSTONE/GOG-3032: Interim Analysis of a Phase 2 Study of Niraparib + Dostarlimab in Patients (Pts) with Platinum-Resistant Ovarian Cancer (PROC). J. Clin. Oncol. 2022, 40, 5573. [Google Scholar] [CrossRef]
  357. Konstantinopoulos, P.A.; Waggoner, S.; Vidal, G.A.; Mita, M.; Moroney, J.W.; Holloway, R.; van Le, L.; Sachdev, J.C.; Chapman-Davis, E.; Colon-Otero, G.; et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019, 5, 1141–1149. [Google Scholar] [CrossRef] [Green Version]
  358. de Bono, J.; Ramanathan, R.K.; Mina, L.; Chugh, R.; Glaspy, J.; Rafii, S.; Kaye, S.; Sachdev, J.; Heymach, J.; Smith, D.C.; et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov 2017, 7, 620. [Google Scholar] [CrossRef] [Green Version]
  359. Piha-Paul, S.A.; Xiong, W.W.; Moss, T.; Mostorino, R.M.; Sedelmeier, S.; Hess, K.; Fu, S.; Hong, D.; Janku, F.; Karp, D.; et al. Abstract A096: Phase II Study of the PARP Inhibitor Talazoparib in Advanced Cancer Patients with Somatic Alterations in BRCA1/2, Mutations/Deletions in PTEN or PTEN Loss, Aberrations in Other BRCA Pathway Genes, and Germline Mutations in BRCA1/2 (Not Breast or Ovarian Cancer). Mol Cancer Ther 2018, 17, A096. [Google Scholar] [CrossRef]
  360. Schram, A.M.; Colombo, N.; Arrowsmith, E.; Narayan, V.; Yonemori, K.; Scambia, G.; Zelnak, A.; Bauer, T.M.; Jin, N.; Ulahannan, S.v.; et al. Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial. JAMA Oncol. 2022. [Google Scholar] [CrossRef]
  361. Yap, T.A.; Bardia, A.; Dvorkin, M.; Galsky, M.D.; Thaddeus Beck, J.; Wise, D.R.; Karyakin, O.; Rubovszky, G.; Kislov, N.; Rohrberg, K.; et al. Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial. JAMA Oncol. 2022. [Google Scholar] [CrossRef]
  362. Wu, X.; Zhu, J.; Wang, J.; Lin, Z.; Yin, R.; Sun, W.; Zhou, Q.; Zhang, S.; Wang, D.; Shi, H.; et al. Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study. Clin. Cancer Res. 2022, 28, 653–661. [Google Scholar] [CrossRef] [PubMed]
  363. Johnson, M.; Galsky, M.; Barve, M.; Goel, S.; Park, H.; Du, B.; Mu, S.; Ramakrishnan, V.; Wood, K.; Wang, V.; et al. Preliminary Results of Pamiparib (BGB-290), a PARP1/2 Inhibitor, in Combination with Temozolomide (TMZ) in Patients (Pts) with Locally Advanced or Metastatic Solid Tumors. Ann. Oncol. 2018, 29, viii138. [Google Scholar] [CrossRef]
  364. Kristeleit, R.; Shapiro, G.I.; Burris, H.A.; Oza, A.M.; LoRusso, P.; Patel, M.R.; Domchek, S.M.; Balmaña, J.; Drew, Y.; Chen, L.M.; et al. A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors. Clin. Cancer Res. 2017, 23, 4095–4106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  365. Shapiro, G.I.; Kristeleit, R.S.; Burris, H.A.; LoRusso, P.; Patel, M.R.; Drew, Y.; Giordano, H.; Maloney, L.; Watkins, S.; Goble, S.; et al. Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors. Clin Pharmacol Drug Dev 2019, 8, 107. [Google Scholar] [CrossRef]
  366. Swisher, E.M.; Lin, K.K.; Oza, A.M.; Scott, C.L.; Giordano, H.; Sun, J.; Konecny, G.E.; Coleman, R.L.; Tinker, A.v.; O’Malley, D.M.; et al. Rucaparib in Relapsed, Platinum-Sensitive High-Grade Ovarian Carcinoma (ARIEL2 Part 1): An International, Multicentre, Open-Label, Phase 2 Trial. Lancet Oncol. 2017, 18, 75–87. [Google Scholar] [CrossRef]
  367. Swisher, E.M.; Kwan, T.T.; Oza, A.M.; Tinker, A.v.; Ray-Coquard, I.; Oaknin, A.; Coleman, R.L.; Aghajanian, C.; Konecny, G.E.; O’Malley, D.M.; et al. Molecular and Clinical Determinants of Response and Resistance to Rucaparib for Recurrent Ovarian Cancer Treatment in ARIEL2 (Parts 1 and 2). Nat. Commun. 2021, 12. [Google Scholar] [CrossRef] [PubMed]
  368. Coleman, R.L.; Oza, A.M.; Lorusso, D.; Aghajanian, C.; Oaknin, A.; Dean, A.; Colombo, N.; Weberpals, J.I.; Clamp, A.; Scambia, G.; et al. Rucaparib Maintenance Treatment for Recurrent Ovarian Carcinoma after Response to Platinum Therapy (ARIEL3): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet 2017, 390, 1949. [Google Scholar] [CrossRef] [Green Version]
  369. Ledermann, J.A.; Oza, A.M.; Lorusso, D.; Aghajanian, C.; Oaknin, A.; Dean, A.; Colombo, N.; Weberpals, J.I.; Clamp, A.R.; Scambia, G.; et al. Rucaparib for Patients with Platinum-Sensitive, Recurrent Ovarian Carcinoma (ARIEL3): Post-Progression Outcomes and Updated Safety Results from a Randomised, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2020, 21, 710–722. [Google Scholar] [CrossRef]
  370. Colombo, N.; Oza, A.M.; Lorusso, D.; Aghajanian, C.; Oaknin, A.; Dean, A.; Weberpals, J.I.; Clamp, A.R.; Scambia, G.; Leary, A.; et al. The Effect of Age on Efficacy, Safety and Patient-Centered Outcomes with Rucaparib: A Post Hoc Exploratory Analysis of ARIEL3, a Phase 3, Randomized, Maintenance Study in Patients with Recurrent Ovarian Carcinoma. Gynecol. Oncol. 2020, 159, 101. [Google Scholar] [CrossRef]
  371. Kristeleit, R.; Lisyanskaya, A.; Fedenko, A.; Dvorkin, M.; de Melo, A.C.; Shparyk, Y.; Rakhmatullina, I.; Bondarenko, I.; Colombo, N.; Svintsitskiy, V.; et al. Rucaparib versus Standard-of-Care Chemotherapy in Patients with Relapsed Ovarian Cancer and a Deleterious BRCA1 or BRCA2 Mutation (ARIEL4): An International, Open-Label, Randomised, Phase 3 Trial. Lancet Oncol. 2022, 23, 465–478. [Google Scholar] [CrossRef]
  372. Yubero-Esteban, A.; Barquin, A.; Estévez, P.; Pajares Hachero, B.; Sánchez, L.; Reche, P.; Alarcón, J.; Calzas, J.; Gaba, L.; Fuentes-Pradera, J.; et al. 403 Analysis of the Clinical Experience within Rucaparib’s Early Access Program in Spain – a GEICO Study. Int. J. Gynecol. Cancer 2021, 31, A232.2–A233. [Google Scholar] [CrossRef]
  373. Lorusso, D.; Maltese, G.; Sabatucci, I.; Cresta, S.; Matteo, C.; Ceruti, T.; D’Incalci, M.; Zucchetti, M.; Raspagliesi, F.; Sonetto, C.; et al. Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile. Target. Oncol. 2021, 16, 59–68. [Google Scholar] [CrossRef] [PubMed]
  374. Dumbrava, E.E.; Shapiro, G.; Bendell, J.C.; Yap, T.A.; Jeselsohn, R.; Lepley, D.M.; Hurley, S.; Lin, K.K.; Liao, M.; Habeck, J.; et al. Phase 1b/2 SEASTAR Trial: Safety, Pharmacokinetics, and Preliminary Efficacy of the Poly(ADP)-Ribose Polymerase (PARP) Inhibitor Rucaparib and Angiogenesis Inhibitor Lucitanib in Patients with Advanced Solid Tumors. J. Clin. Oncol. 2021, 39, 3102. [Google Scholar] [CrossRef]
  375. Yap, T.A.; Hamilton, E.; Bauer, T.; Dumbrava, E.E.; Jeselsohn, R.; Enke, A.; Hurley, S.; Lin, K.K.; Habeck, J.; Giordano, H.; et al. Phase Ib SEASTAR Study: Combining Rucaparib and Sacituzumab Govitecan in Patients With Cancer With or Without Mutations in Homologous Recombination Repair Genes. JCO Precis. Oncol. 2022, 6. [Google Scholar] [CrossRef] [PubMed]
  376. Monk, B.J.; Parkinson, C.; Lim, M.C.; O’malley, D.M.; Oaknin, A.; Wilson, M.K.; Coleman, R.L.; Lorusso, D.; Bessette, P.; Ghamande, S.; et al. A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-Ov45). J. Clin. Oncol. 2022, 40. [Google Scholar] [CrossRef]
Cancers 15 00448 g001 550
Figure 1. Simplified representation of the DNA damage response (DDR) activated by endogenous or exogenous DNA-damaging agents. This figure has been created using images from BioRender.com and Flaticon.com.
Figure 1. Simplified representation of the DNA damage response (DDR) activated by endogenous or exogenous DNA-damaging agents. This figure has been created using images from BioRender.com and Flaticon.com.
Cancers 15 00448 g001
Cancers 15 00448 g002 550
Figure 2. Schematic representation of the five major DNA repair pathways and the proteins involved. This figure has been created using images from BioRender.com and Flaticon.com.
Figure 2. Schematic representation of the five major DNA repair pathways and the proteins involved. This figure has been created using images from BioRender.com and Flaticon.com.
Cancers 15 00448 g002
Table
Table 1. Clinical characteristics and genetic alterations in the five different subtypes of epithelial OC [2,5].
Table 1. Clinical characteristics and genetic alterations in the five different subtypes of epithelial OC [2,5].
SubtypeHigh-Grade SerousEndometrioidClear cellMucinousLow-Grade Serous
Prevalence70%10%10%5%<5%
Stage at diagnosisAdvancedEarlyEarlyEarlyEarly or advanced
Progression speedHighLow (90%)
High (10%)		LowLow (50%)
High (50%)		Low
Genetic alterationsTP53
BRCA1
BRCA2		CTNNB1
PIK3CA
ARID1A
KRAS
PPP2R1
PTEN		ARID1A
PTEN
PIK3CA
KRAS
MET		KRAS
TP53
HER2/Neu		BRAF
KRAS
HER2/Neu
Chemotherapeutic responseHigh (at early stages)LowLowLowLow
Table
Table 2. Main proteins involved in each DDR pathway.
Table 2. Main proteins involved in each DDR pathway.
DDR PathwayProteins Involved (References)
DRMGMT [28]
MMRSensorsMSH2, MSH6, MLH1, PMS1, PMS2, and MSH3 [29,30,31]
TransducersRPA, PCNA, and RFC [32]
EffectorsExo1, Pol δ, and DNA ligase I [32,33]
NERSensorsTC-NER RNA polymerase, CSA, CSB, and XAB2 [26,34]
GG-NERXPC-RAD23B and UV-DDB [26,34]
TransducersXPA, XPG, XPF/ERCC1, RPA, TFIIH complex [34,35]
EffectorsPCNA, RFC, DNA polymerases δ, ε, and κ, and DNA ligase I and LIG3 [34,35]
BERSensorsDNA glycosylase (OGG1, UNG, or MUTYH), APE1, and PARP1 [36]
TransducersPNKP [37,38]
EffectorsXRCC1, LIG3, DNA polymerase β [37,38]
HRSensorsMRN complex (MRE11, RAD50, NSB1) [39,40]
TransducersATM, BRCA1, ATR, RPA, PALB2, BRCA2 [41,42]
EffectorsRAD51, DNA ligase, DNA polymerase [39,40]
NHEJSensorsC-NHEJKu70, Ku80 [43,44]
Alt-NHEJPARP1 [45,46]
TransducersDNA-PKcs, ATM, ATR, and Artemis [43,44]
EffectorsC-NHEJXRCC4, XLF, and DNA ligase IV [43,44]
Alt-NHEJXRCC1, DNA polymerase Θ, and LIG3 [45,46]
Associated
pathways		Chromatin
remodelers		SWI/SNF, INO80, CHD, ISWI [47]
Checkpoints factorsTransducersATM, ATR, CHK1, CHK2 [48]
Effectorsp53, p21, CDC25C, WEE1, CDK1, CDK2 [48,49,50]
Table
Table 3. DDR alterations in OCs.
Table 3. DDR alterations in OCs.
DDR PathwayGenomic/Epigenomic Alterations in OC (References)
DRMGMT promoter hypermethylation [51,52]
MMRMutations in MLH1, MSH2, MSH6, and PMS2 [53,54,55]
MLH1 promoter hypermethylation [56,57,58]
NERSNPs in NER genes [59]
Homozygous deletions, missense, or splice site mutations in NER genes [60,61]
BERSNPs in OGG1, APE1, and XRCC1 [62,63,64,65,66,67,68]
APE1 overexpression [69]
HRGenetic and epigenetic modifications of genes encoding HR proteins [70,71,72]
Mutations in BRCA1, BRCA2, RAD51C, RAD51D and MRN complex genes [70,71,72,73,74,75,76]
Downregulation of RAD50 [75,77]
RAD51 promoter hypermethylation [60]
NHEJMutations or overexpression of genes that encoded for NHEJ proteins (DNA-PKs, DNA polymerase Θ, or XRCC4) [60,78,79,80]
SNPs in NHEJ genes (DNA ligase IV, XRCC1) [60]
Chromatin remodelersMutations in ARID1A [81,82,83,84]
Mutations in CHD4 [85,86,87], CHD5 [88], and CHD8 [88] subunits
Amplification of CHD4 [85,89] and ACT6LA [88,90] subunits
Checkpoints factorsMutations in ATM [91,92]
Somatic mutations in CHK2 [93]
p53 pathwayMutations in TP53 [94,95]
Loss of heterozygosity in the chromosome that contains TP53 [96]
Table
Table 4. DDR-targeting drugs investigated in preclinical studies.
Table 4. DDR-targeting drugs investigated in preclinical studies.
DDR PathwayDrugTarget(s)Preclinical Evidence(s) in OC Cells or Xenograft Models
DRPaTrin-2MGMTSensitization to temozolomide [97]
NERMCI13ERPAAntitumor activity [98]
TDRL-505RPAAntitumor activity [98]
TDRL-551RPAAntitumor activity and synergistic cytotoxic effect in combination with etoposide and platinum [98]
Trabectedin/
Lurbinectedin		NER and HR proteinsAntitumor activity and synergistic cytotoxic effect in combination with cisplatin, doxorubicin, and irinotecan [99,100,101,102]
BERMethoxyamineAPE1Enhancement of temozolomide cytotoxicity [103]
E3330 and
analogs		APE1Inhibition of cell proliferation [104,105]
Spiclomazine/
fiduxosin		APE1/NPM1 interactionInhibition of cell proliferation and sensitization to bleomycin [106]
PARPiPARPSpecific killing of BRCA-deficient tumors [107,108]
HRMirinMre11Increase sensitivity to DNA-damaging agents (cisplatin, carboplatin, chloroquine) [109,110,111]
PanobinostatRad51Inhibition of OC cell proliferation, induction of apoptosis, and inhibition of DNA repair by altering the correct repair of Rad51 [109,112,113]. Synergistic cytotoxic effect in combination with chloroquine or cisplatin [109,114]
Ellagic acid/
luteolin		MRN
complex		Decrease cellular proliferation and migration [115]
NHEJNU-7026/NU-7441DNA-PKs Enhancement of DNA-damaging agents’ cytotoxicity (irradiation, chloroquine, cisplatin) [116,117,118]
PeposertibDNA-PKsIncrease radiosensitivity and chemosensitivity to etoposide or doxorubicin [119,120]
AZD7648DNA-PKsIncrease the cytotoxicity to irradiation, doxorubicin, or PARP inhibitors [121,122]
Checkpoints
factors		KU-60019ATMInhibition of cell migration and induction of apoptosis [123]. Synergistic cytotoxic effect in combination with fenofibrate (PPARA inhibitor) [123]. Sensitization to ionizing radiation, trabectedin, and lurbinectedin [124,125]
AZD0156ATMSynergistic cytotoxic effect in combination with fenofibrate (PPARA inhibitor) [123]
KU-55933ATMSensitization to ionizing radiation, trabectedin and lurbinectedin [124,125]
AZD1390ATMSynergistic cytotoxic effect in combination with an aldehyde dehydrogenase 1 inhibitor (67A) [126].
VE-821 ATRInhibit cell proliferation and enhancement of cisplatin, topotecan, gemcitabine, and veliparib cytotoxicity [127,128,129,130,131]. Enhancement of lurbinectedin and trabectedin cytotoxicity in combination with KU-60019 [125]
AZ20ATRSensitize PARPi-resistant cells to PARPi [131]
CeralasertibATRSynergistic cytotoxic effect in combination with belotecan, an aldehyde dehydrogenase 1 inhibitor (67A), and PARPi [126,132,133,134,135]
BerzosertibATRReduction of cell proliferation and cell survival [127,129,136,137]
EPT-46464ATRSynergistic cytotoxic effect in combination with cisplatin, carboplatin, and radiation [124]
NU6027ATR/
CDK2		Enhancement of the cytotoxic effect of cisplatin and temozolomide [138]
ElimusertibATRInhibition of cell proliferation [139,140] and enhancement of the cytotoxic effect of carboplatin and therapeutic radiopharmaceuticals [141,140]
GartisertibATREnhancement of topotecan, irinotecan, gemcitabine, cisplatin, and talazoparib cytotoxicity [142]
SRA737CHK1Synergistic cytotoxic effect in combination with PARPi [143]
V158411CHK1Inhibition of cell proliferation and enhancement of carboplatin and cisplatin cytotoxicity [144]
MK-8776CHK1Inhibition of cell proliferation and enhancement of gemcitabine and olaparib efficacy [128,133,145]
PF-477736CHK1Synergistic antiproliferative effect in combination with topotecan [146]
PV1019CHK2Inhibition of cell proliferation and synergistic cytotoxic effect in combination with topotecan or camptothecins [147]
PHI-101CHK2Antitumor activity [148]
C3742CHK2Synergistic cytotoxic effect in combination with cisplatin [149]
AZD7762CHK2Synergistic cytotoxic effect in combination with cisplatin [150]. Sensitization to PARG inhibition [151]
PrexasertibCHK1/
CHK2		Antitumor activity and synergistic cytotoxic effect in combination with olaparib or gemcitabine [128,152,153]
AdavosertibWEE1Antitumor activity, and inhibition of cell proliferation and migration. Induction of DNA damage, apoptosis, and G2/M cell cycle arrest [154]. Synergistic cytotoxic effect in combination with ATR inhibitor (AZD6738) [155], CHK1inhibitor (PF-00477736) [156], and radioimmunotherapy [157]
p53 pathwayPRIMA-1Mutated p53Induction of cell death and re-sensitization of chemoresistant-cells to cisplatin [158,159]
PRIMA-1METMutated p53Re-sensitization of cisplatin/doxorubicin-cells to cisplatin/doxorubicin [160].
Synergistic cytotoxic effect in combination with cisplatin, carboplatin, or doxorubicin [160,161]
ReACP53Mutated p53Cell proliferation decrease and synergistic cytotoxic effect in combination with carboplatin [162,163]
Nutlin MDM2Reduction of cell viability, induction of apoptosis, and synergistic cytotoxic effect in combination with cisplatin, rucaparib, or etoposide [164,165,166,167,168]
RG7388MDM2Reduction of cell viability, induction of apoptosis, and synergistic cytotoxic effect in combination with cisplatin, rucaparib, or etoposide [164,167,169]
RG7112MDM2Cell growth reduction [170]
Drugs in bold have been tested in clinical trials.
Table
Table 5. DDR-targeting drugs investigated in clinical studies in monotherapy or in combination with other antitumor drugs.
Table 5. DDR-targeting drugs investigated in clinical studies in monotherapy or in combination with other antitumor drugs.
DDR
Pathway		Target(s)DrugCombined withConditionPhaseClinical IDResults
DRMGMTPaTrin-2TemozolomideOCI[171]One patient with OC has a decrease of around 50% of tumor markers and stable radiology over 5–6 cycles of treatment [171]
NERNER and HR
proteins		Trabectedin-Advanced OCIINCT00050414Trabectedin was active and well-tolerated in advanced OC platinum-sensitive patients. The optimal regimen was established [172]
Advanced tumor malignanciesIINCT00786838Trabectedin efficacy was confirmed [173]
Advanced soft tissue sarcomasIINCT00003939Trabectedin has proven to control tumor progression in highly pretreated, progression, advanced, metastatic resistant, or refractory sarcoma patients [174]
Ovarian carcinosarcomaIINCT02993705Trabectedin conferred a modest benefit to patients with advanced OC and it was well-tolerated [175]
BRCA mutated OCII
III		NCT01772979
NCT02903004		OC patients with BRCAness phenotype could benefit from trabectedin treatment. However, this treatment did not improve survival compared to standard chemotherapy in BRCA-mutated and BRCAness phenotype OC patients [176,177]
PLDRelapsed OCIINCT04887961No results posted
Partially platinum-sensitive OCIIINCT01379989Trabectedin/PLD combination showed a similar overall survival that carboplatin/PLD combination and could be considered for treating patients who need a longer recovery time from platinum toxicities [178]
Advanced relapsed OCIIINCT00113607
NCT01846611		Trabectedin/PLD combination did not show a favorable overall survival benefit or safety. Specifically, patients with BRCA-mutation or a platinum-free interval of 6–12 months seemed to present a survival benefit from this combination [179,180,181,182]
Recurrent OCIIINCT03690739No results posted
Platinum-sensitive recurrent OCIVNCT03164980OC patients treated with trabectedin/PLD did not show inferiority signals compared to standard platinum-based chemotherapy. The study is ongoing and recruiting new patients [183]
Platinum-sensitive recurrent OCObservationalNCT02394015
NCT05512676		The intercalation with a nonplatinum regimen, such as trabectedin/PLD, could improve the response to a platinum-base therapy platinum-sensitive OC patients [184]
Partially platinum-sensitive recurrent OCObservationalNCT03446495No results posted
Relapsed OCObservationalNCT02825420The combination of trabectedin and PLD represented a therapeutical safe option for platinum-sensitive recurrent OC regardless of prior anti-angiogenic treatment [185]
Platinum-sensitive relapsed OCObservationalNCT02163720
NCT01869400		PLD/trabectedin supposed a therapeutic option for partially or fully platinum-sensitive recurrent OC patients [186,187]
PLD +/− olaparibRecurrent OCIINCT03470805No results posted
DurvalumabOCINCT03085225The combination of trabectedin and durvalumab presented a manageable toxicity and a promising antitumor activity in platinum-refractory OC patients [188]
Docetaxel + pegfilgrastim/filgastrimRecurrent or persistent OCIINCT00569673Docetaxel/trabectedin was well-tolerated and seemed to be more active than docetaxel treatment in recurrent OC patients [189]
Bevacizumab +/− carboplatinRecurrent OCIINCT01735071Bevacizumab/trabectedin combination had clinical activity and could be a therapeutic option for partially platinum-sensitive OC patients. Bevacizumab/trabectedin/carboplatin demonstrated a positive activity and should be further studied [190]
LurbinectedinPaclitaxel +/− bevacizumabAdvanced solid tumorsINCT01831089Lubinectedin combined with paclitaxel and/or bevacizumab presented a manageable toxicity and promising antitumor activity in patients with advanced solid tumors, including OC [191]
OlaparibAdvanced solid tumorsI/IINCT02684318Lurbinectedin/olaparib combination was feasible and recommended doses were obtained for each drug [192]
IrinotecanSolid tumorsI/IINCT02611024One OC BRCA1-mutated patient presented an extraordinary response with a time to further progression of 8 months. No more results have been posted [193]
BERAPE1Methoxyamine-Platinum-resistant OCIIINCT02421588Lurbinectedin showed antitumor activity similar to PLD and it was better tolerated [194]
TemozolomideGranulosa cell OCI/IINCT01851369Two patients with granulosa cell OC experienced a partial response [195]
Permetrexed + cisplatinAdvanced solid tumorsI/IINCT02535312No results posted
PARPOlaparibDescribed in Table S1
Niraparib
Talazoparib
Pamiparib
Rucaparib
HRRad51Panobinostat-Advanced solid tumorsINCT00739414Panobinostat treatment was safe and potentially effective against advanced solid tumors like OC [196]
GemcitabineSolid tumorsINCT00550199Recommended doses for panobinostat/gemcitabine were established [197]
NHEJDNA-PKsPeposertibPLDRecurrent OCINCT04092270No results posted
Checkpoints
factors		ATRCeralasertibOlaparibRecurrent OCIINCT03462342The combination of ceralasertib and olaparib was well-tolerated. No objective response was observed; however, a signal of activity was observed and depended on BRCA1 status [198]
Recurrent OCIINCT03579316No results posted about ceralasertib/olaparib combination
Gynecological cancersIINCT04065269No results posted
Advanced solid tumorsIINCT02576444Ceralasertib/olaparib combination has demonstrated preliminary activity in ATM-mutated tumors and in BRCA-mutated PARPi-resistant HGSC OC patients [199]
Carboplatin/Olaparib/DurvalumabAdvanced tumorsINCT02264678No results posted
BerzosertibCarboplatin + GemcitabineRecurrent and metastatic OCINCT02627443No results posted
Carboplatin + AvelumabPARPi resistant, recurrent, and platinum sensitive OCINCT03704467Berzosertib/carboplatin/carboplatin safe doses were established; however, phase II was not started [200]
Gemcitabine/Cisplatin/Etoposide/Carboplatin/IrinotecanAdvanced solid tumorsINCT02157792Berzosertib/cisplatin and berzosertib/carboplatin combinations were well-tolerated and presented preliminary preclinical activity in patients with advanced solid tumors, including OC patients. [201,202]
TopotecanOvarian neoplasmsINCT02487095Only one patient with OC was recruited, this patient presented a short duration of the response and a progressive disease [203]
GemcitabineRecurrent OCIINCT02595892The addition of berzosertib to gemcitabine in platinum-resistant HGSC increased PFS rate compared to gemcitabine in monotherapy [204]
GartisertibNiraparibPARPi resistant and recurrent OCINCT04149145Not yet recruiting patients
ElimusertibNiraparibAdvanced OCINCT04267939No results posted
GemcitabineAdvanced OCINCT04616534No results posted
Gemcitabine +/− CisplatinAdvanced OCINCT04491942No results posted
CHK1SRA737-HGSC OC with/without CCNE1 gene amplificationI/IINCT02797964SRA737-maximum tolerated dose was established. Based on tolerability and pharmacokinetics, phase II was recommended [205]
Gemcitabine +/− CisplatinHGSC OCI/IINCT02797977Low-dose gemcitabine combined with SRA737 has been well-tolerated in HGSC OC patients [206]
LY2880070+/− GemcitabineAdvanced or metastatic OCI/IINCT02632448LY2880070 together with low-dose gemcitabine was well-tolerated [207]
CHK2PHI-101-Platinum-resistant or refractory OCINCT04678102No results posted
CHK1/
CHK2		Prexasertib-Platinum-resistant or refractory OCIINCT03414047Prexasertib has demonstrated durable single agent activity in a subset of OC patients regardless their clinical characteristics, BRCA status of prior therapies [208]
-HGSC OC with/without BRCA mutationsIINCT02203513Prexasertib presented clinical activity and was tolerable in HGSC OC patients with BRCA-wild type [209]
OlaparibAdvanced solid tumorsINCT03057145The combination of prexasertib and olaparib had preclinical activity in BRCA-mutant HGSC OC patients who had previously progressed on a PARPi [210]
WEE1Adavosertib-Advanced OCINCT02659241No results posted
Carboplatin/Paclitaxel/Gemcitabine/PLDPlatinum-resistant OCIINCT022727903% of platinum-resistant OC patients presented a completed response and 29% a partial response. The highest response rate was obtained with adavosertib/carboplatin combination [211]
CarboplatinTP53-mutated refractory and resistant OCIINCT01164995Adavosertib/carboplatin combination demonstrated a manageable toxicity. The overall response rate was 43% and one patient (5%) presented prolonged complete response [212]
GemcitabineRecurrent OCIINCT02101775Recurrent OC patients-treated with adavosertib/gemcitabine presented a longer PFS [213]
Paclitaxel + carboplatinTP53-mutated platinum- sensitive OCIINCT01357161The addition of adavosertib to chemotherapy treatment (paclitaxel/carboplatin) improved PFS [214]
OlaparibRecurrent OC
Refractory solid tumors
Advanced solid tumors		II
I
II		NCT03579316
NCT02511795
NCT02576444		Adavosertib in monotherapy or combined with olaparib demonstrated efficacy in patients with resistance to PARPi. Adavosertib/olaparib combination presented manageable toxicities [215,216,217]
ZN-c3NiraparibPlatinum-resistant OCI/IINCT05198804No results posted, recruiting patients
p53 pathwayMutated p53PRIMA-1METPLDPlatinum-resistant HGSC OCIINCT0326838236 patients were enrolled in this study which have been treated with several doses of PLD and APR-246. That combination was feasible and adverse effects were manageable
+/− Carboplatin/PLDRecurrent HGSC OCI/IINCT02098343APR-246/carboplatin or APR-246/PLD combinations were effective in HGSC OC patients with TP53-mutated and recommended phase II dose has been established [218]
HGSC: high-grade serous carcinoma; PARPi: PARP inhibitor; PLD: pegylated liposomal doxorubicin; PFS: progression-free survival; ORR: objective response ratio; OS: overall survival.
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Ovejero-Sánchez, M.; González-Sarmiento, R.; Herrero, A.B. DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities. Cancers 2023, 15, 448. https://doi.org/10.3390/cancers15020448

AMA Style

Ovejero-Sánchez M, González-Sarmiento R, Herrero AB. DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities. Cancers. 2023; 15(2):448. https://doi.org/10.3390/cancers15020448

Chicago/Turabian Style

Ovejero-Sánchez, María, Rogelio González-Sarmiento, and Ana Belén Herrero. 2023. "DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities" Cancers 15, no. 2: 448. https://doi.org/10.3390/cancers15020448

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