Editorial

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Open AccessEditorial

The Impact of DNA Repair Pathways in Cancer Biology and Therapy

by Anatoly Nikolaev and Eddy S. Yang

Cancers 2017, 9(9), 126; https://doi.org/10.3390/cancers9090126 - 19 Sep 2017

Cited by 14 | Viewed by 4204

Abstract

Genomic instability is one of the key hallmarks of cancer progression [1].[...] Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

Research

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Open AccessArticle

Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach

by Zacharenia Nikitaki, Athanasia Pavlopoulou, Marcela Holá, Mattia Donà, Ioannis Michalopoulos, Alma Balestrazzi, Karel J. Angelis and Alexandros G. Georgakilas

Cancers 2017, 9(6), 65; https://doi.org/10.3390/cancers9060065 - 06 Jun 2017

Cited by 11 | Viewed by 6298

Abstract

The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals [...] Read more.

The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a ‘plant radiation biodosimeter’, that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana—based plant system monitoring the role of cancer-related DNA repair genes BRCA1, BARD1 and PARP1 in processing DNA lesions. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Review

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Open AccessReview

Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors

by Joline S. J. Lim and David S. P. Tan

Cancers 2017, 9(8), 109; https://doi.org/10.3390/cancers9080109 - 22 Aug 2017

Cited by 37 | Viewed by 14383

Abstract

Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors [...] Read more.

Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Open AccessReview

The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

by Brock J. Sishc and Anthony J. Davis

Cancers 2017, 9(7), 81; https://doi.org/10.3390/cancers9070081 - 06 Jul 2017

Cited by 108 | Viewed by 12247

Abstract

DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect [...] Read more.

DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ’s role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Open AccessReview

Carbon Ion Radiotherapy: A Review of Clinical Experiences and Preclinical Research, with an Emphasis on DNA Damage/Repair

by Osama Mohamad, Brock J. Sishc, Janapriya Saha, Arnold Pompos, Asal Rahimi, Michael D. Story, Anthony J. Davis and D.W. Nathan Kim

Cancers 2017, 9(6), 66; https://doi.org/10.3390/cancers9060066 - 09 Jun 2017

Cited by 122 | Viewed by 13790

Abstract

Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions [...] Read more.

Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions that overwhelm the DNA repair capacity of malignant cells. These physical and radiobiological characteristics imbue heavy ions with potent tumoricidal capacity, while having the potential for simultaneously maximally sparing normal tissues. Thus, CIRT could potentially be used to treat some of the most difficult to treat tumors, including those that are hypoxic, radio-resistant, or deep-seated. Clinical data, mostly from Japan and Germany, are promising, with favorable oncologic outcomes and acceptable toxicity. In this manuscript, we review the physical and biological rationales for CIRT, with an emphasis on DNA damage and repair, as well as providing a comprehensive overview of the translational and clinical data using CIRT. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Open AccessReview

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

by Laura Annovazzi, Marta Mellai and Davide Schiffer

Cancers 2017, 9(6), 57; https://doi.org/10.3390/cancers9060057 - 26 May 2017

Cited by 59 | Viewed by 11322

Abstract

Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize [...] Read more.

Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Open AccessReview

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

by Govindi J. Samaranayake, Mai Huynh and Priyamvada Rai

Cancers 2017, 9(5), 47; https://doi.org/10.3390/cancers9050047 - 08 May 2017

Cited by 48 | Viewed by 7314

Abstract

Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated [...] Read more.

Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Open AccessReview

Targeting the ATR-CHK1 Axis in Cancer Therapy

by Stuart Rundle, Alice Bradbury, Yvette Drew and Nicola J. Curtin

Cancers 2017, 9(5), 41; https://doi.org/10.3390/cancers9050041 - 27 Apr 2017

Cited by 160 | Viewed by 16909

Abstract

Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article [...] Read more.

Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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Open AccessReview

DNA Repair Pathway Alterations in Bladder Cancer

by Kent W. Mouw

Cancers 2017, 9(4), 28; https://doi.org/10.3390/cancers9040028 - 27 Mar 2017

Cited by 38 | Viewed by 6651

Abstract

Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may [...] Read more.

Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy. In addition, tumor DNA repair defects have important implications for use of immunotherapy and other targeted agents in bladder cancer. Therefore, efforts to further understand the landscape of DNA repair alterations in bladder cancer will be critical in advancing treatment for bladder cancer. This review summarizes the current understanding of the role of DNA repair pathway alterations in bladder tumor biology and response to therapy. Full article

(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

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