Cancer Therapy Resistance: Choosing Kinase Inhibitors

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 35402

Special Issue Editors

1. Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS)-National Research Council (CNR), 80131 Napoli, Italy
2. Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
Interests: miRNA; extracellular vesicless; drug discovery; epigenetics; cancerogenesis; pharmacoresistance; cancer therapy
Special Issues, Collections and Topics in MDPI journals
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: cancer; epigenetics; hormone signaling; drug discovery
Special Issues, Collections and Topics in MDPI journals
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: drug discovery; cancer; epigenetics; pharmaceutical chemistry; enzymatic assay
Special Issues, Collections and Topics in MDPI journals
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: bioinformatics; single cell genomics; epigenetics; cancer
Division of Pharmacology, Department of Experimental Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
Interests: heart failure with preserved ejection fraction; anthracycline cardiotoxicity; diastolic dysfunction

Special Issue Information

Dear Colleagues,

Despite the prominent efforts and achievements in cancer treatment, cancer resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in clinical oncology. The advent of multiple omics techniques has provided a broader understanding of the tumor heterogeneity and drug resistance mechanisms in human cancer. The key mechanisms of intrinsic and acquired resistance to cancer therapy include (1) pre-existing or secondary genetic alterations in the drug target; (2) activation of bypass signaling pathways involving second driver proto-oncogenes; (3) heterogeneity of tumor subpopulations, including cancer stem cells; and (4) alteration of the tumor microenvironment (TME), including immune evasion.

The data integration of epigenomics, transcriptomics, proteomics, and metabolomics has allowed defining the complex functional role of kinase networks in molecular mechanisms driving resistance.

The targeting of kinases represents a new therapeutic paradigm in the clinical challenge of overcoming resistance. This Special Issue aims to exploit promising findings and innovative therapeutic strategies to overcome cancer drug resistance. We welcome both original research articles and topical reviews with a strong focus on hot kinase-mediated molecular mechanisms driving resistance and novel therapeutic options with kinase inhibitor (KI) agents, or combination therapies, including pharmaceutics strategies and technologies for drug optimization. We especially welcome submissions about immune evasion and tumor heterogeneity mediated by kinase networks, including exciting studies using liquid biopsy approaches to assess resistance, particularly when coupled with next-generation sequencing strategies.

This Special Issue seeks to provide a tie between pharmaceutics and oncology by offering some valuable and innovative approaches to realize the process from bench to bedside.

Dr. Carmela Dell’Aversana
Dr. Rosaria Benedetti
Dr. Federica Sarno
Dr. Wouter Leonard Megchelenbrink
Dr. Donato Cappetta
Guest Editors

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Keywords

  • kinase inhibitors
  • cancer drug resistance
  • targeted therapy
  • drug discovery
  • genetic mutation
  • epigenetic modifications
  • alternative splicing
  • epitranscriptome
  • liquid biopsy
  • next-generation sequencing
  • immune evasion
  • tumor heterogeneity

Published Papers (12 papers)

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Editorial

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6 pages, 189 KiB  
Editorial
Cancer Therapy Resistance: Choosing Kinase Inhibitors
by Carmela Dell’Aversana, Federica Sarno, Rosaria Benedetti, Wouter Leonard Megchelenbrink and Donato Cappetta
Pharmaceutics 2024, 16(3), 373; https://doi.org/10.3390/pharmaceutics16030373 - 07 Mar 2024
Viewed by 411
Abstract
Recent advances in comprehending the essential molecular mechanisms that govern cancer signaling have revealed the pivotal involvement of kinases in the development and progression of various cancer types [...] Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)

Research

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17 pages, 2621 KiB  
Article
Synthesis and Biological Properties of EGFR-Targeted Photosensitizer Based on Cationic Porphyrin
by Yulia S. Bortnevskaya, Nikita A. Shiryaev, Nikita S. Zakharov, Oleg O. Kitoroage, Margarita A. Gradova, Natalia Yu. Karpechenko, Alexander S. Novikov, Elena D. Nikolskaya, Mariia R. Mollaeva, Nikita G. Yabbarov, Natal’ya A. Bragina and Kseniya A. Zhdanova
Pharmaceutics 2023, 15(4), 1284; https://doi.org/10.3390/pharmaceutics15041284 - 19 Apr 2023
Cited by 1 | Viewed by 1292
Abstract
Photodynamic therapy (PDT) in oncology is characterized by low invasiveness, minimal side effects, and little tissue scarring. Increasing the selectivity of PDT agents toward a cellular target is a new approach intended to improve this method. This study is devoted to the design [...] Read more.
Photodynamic therapy (PDT) in oncology is characterized by low invasiveness, minimal side effects, and little tissue scarring. Increasing the selectivity of PDT agents toward a cellular target is a new approach intended to improve this method. This study is devoted to the design and synthesis of a new conjugate based on meso-arylporphyrin with a low-molecular-weight tyrosine kinase inhibitor, Erlotinib. A nano-formulation based on Pluronic F127 micelles was obtained and characterized. The photophysical and photochemical properties and biological activity of the studied compounds and their nano-formulation were studied. A significant, 20–40-fold difference between the dark and photoinduced activity was achieved for the conjugate nanomicelles. After irradiation, the studied conjugate nanomicelles were 1.8 times more toxic toward the EGFR-overexpressing cell line MDA-MB-231 compared to the conditionally normal NKE cells. The IC50 was 0.073 ± 0.014 μM for the MDA-MB-231 cell line and 0.13 ± 0.018 μM for NKE cells after irradiation for the target conjugate nanomicelles. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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21 pages, 6283 KiB  
Article
Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer
by Ahmed A. El-Shenawy, Mahmoud M. A. Elsayed, Gamal M. K. Atwa, Mohammed A. S. Abourehab, Mohamed S. Mohamed, Mohammed M. Ghoneim, Reda A. Mahmoud, Shereen A. Sabry, Walid Anwar, Mohamed El-Sherbiny, Yasser A. Hassan, Amany Belal and Abd El hakim Ramadan
Pharmaceutics 2023, 15(2), 680; https://doi.org/10.3390/pharmaceutics15020680 - 17 Feb 2023
Cited by 8 | Viewed by 2142
Abstract
Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the [...] Read more.
Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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19 pages, 2412 KiB  
Article
Synthesis, Physicochemical and Biological Study of Gallium-68- and Lutetium-177-Labeled VEGF-A165/NRP-1 Complex Inhibitors Based on Peptide A7R and Branched Peptidomimetic
by Katarzyna Masłowska, Ewa Witkowska, Dagmara Tymecka, Paweł Krzysztof Halik, Aleksandra Misicka and Ewa Gniazdowska
Pharmaceutics 2022, 14(1), 100; https://doi.org/10.3390/pharmaceutics14010100 - 01 Jan 2022
Cited by 7 | Viewed by 1842
Abstract
Neuropilin-1 (NRP-1) is a surface receptor found on many types of cancer cells. The overexpression of NRP-1 and its interaction with vascular endothelial growth factor-165 (VEGF165) are associated with tumor growth and metastasis. Therefore, compounds that block the VEGF165/NRP-1 [...] Read more.
Neuropilin-1 (NRP-1) is a surface receptor found on many types of cancer cells. The overexpression of NRP-1 and its interaction with vascular endothelial growth factor-165 (VEGF165) are associated with tumor growth and metastasis. Therefore, compounds that block the VEGF165/NRP-1 interaction represent a promising strategy to image and treat NRP-1-related pathologies. The aim of the presented work was to design and synthesize radioconjugates of two known peptide-type inhibitors of the VEGF165/NRP-1 complex: A7R peptide and its shorter analog, the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg. Both peptide-type inhibitors were coupled to a radionuclide chelator (DOTA) via a linker (Ahx) and so radiolabeled with Ga-68 and Lu-177 radionuclides, for diagnostic and therapeutic uses, respectively. The synthesized radioconjugates were tested for their possible use as theranostic-like radiopharmaceuticals for the imaging and therapy of cancers that overexpress NRP-1. The obtained results indicate good efficiency of the radiolabeling reaction and satisfactory stability, at least 3t1/2 for the 68Ga- and 1t1/2 for the 177Lu-radiocompounds, in solutions mimicking human body fluids. However, enzymatic degradation of both the studied inhibitors caused insufficient stability of the radiocompounds in human serum, indicating that further modifications are needed to sufficiently stabilize the peptidomimetics with inhibitory properties against VEGF165/NRP-1 complex formation. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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Review

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26 pages, 1784 KiB  
Review
Triple Negative Breast Cancer Treatment Options and Limitations: Future Outlook
by Onyinyechi Obidiro, Gantumur Battogtokh and Emmanuel O. Akala
Pharmaceutics 2023, 15(7), 1796; https://doi.org/10.3390/pharmaceutics15071796 - 23 Jun 2023
Cited by 12 | Viewed by 3355
Abstract
Triple negative breast cancer (TNBC) has a negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). The survival rate for TNBC is generally worse than other breast cancer subtypes. TNBC treatment has made significant advances, but [...] Read more.
Triple negative breast cancer (TNBC) has a negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). The survival rate for TNBC is generally worse than other breast cancer subtypes. TNBC treatment has made significant advances, but certain limitations remain. Treatment for TNBC can be challenging since the disease has various molecular subtypes. A variety of treatment options are available, such as chemotherapy, immunotherapy, radiotherapy, and surgery. Chemotherapy is the most common of these options. TNBC is generally treated with systemic chemotherapy using drugs such as anthracyclines and taxanes in neoadjuvant or adjuvant settings. Developing resistance to anticancer drugs and off-target toxicity are the primary hindrances to chemotherapeutic solutions for cancer. It is imperative that researchers, clinicians, and pharmaceutical companies work together to develop effective treatment options for TNBC. Several studies have suggested nanotechnology as a potential solution to the problem of suboptimal TNBC treatment. In this review, we summarized possible treatment options for TNBC, including chemotherapy, immunotherapy, targeted therapy, combination therapy, and nanoparticle-based therapy, and some solutions for the treatment of TNBC in the future. Moreover, we gave general information about TNBC in terms of its characteristics and aggressiveness. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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31 pages, 2343 KiB  
Review
Insights into Lipid-Based Delivery Nanosystems of Protein-Tyrosine Kinase Inhibitors for Cancer Therapy
by Josef Jampilek and Katarina Kralova
Pharmaceutics 2022, 14(12), 2706; https://doi.org/10.3390/pharmaceutics14122706 - 03 Dec 2022
Cited by 4 | Viewed by 1831
Abstract
According to the WHO, cancer caused almost 10 million deaths worldwide in 2020, i.e., almost one in six deaths. Among the most common are breast, lung, colon and rectal and prostate cancers. Although the diagnosis is more perfect and spectrum of available drugs [...] Read more.
According to the WHO, cancer caused almost 10 million deaths worldwide in 2020, i.e., almost one in six deaths. Among the most common are breast, lung, colon and rectal and prostate cancers. Although the diagnosis is more perfect and spectrum of available drugs is large, there is a clear trend of an increase in cancer that ends fatally. A major advance in treatment was the introduction of gentler antineoplastics for targeted therapy–tyrosine kinase inhibitors (TKIs). Although they have undoubtedly revolutionized oncology and hematology, they have significant side effects and limited efficacy. In addition to the design of new TKIs with improved pharmacokinetic and safety profiles, and being more resistant to the development of drug resistance, high expectations are placed on the reformulation of TKIs into various drug delivery lipid-based nanosystems. This review provides an insight into the history of chemotherapy, a brief overview of the development of TKIs for the treatment of cancer and their mechanism of action and summarizes the results of the applications of self-nanoemulsifying drug delivery systems, nanoemulsions, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles and nanostructured lipid carriers used as drug delivery systems of TKIs obtained in vitro and in vivo. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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12 pages, 422 KiB  
Review
The Role of the Kinase Inhibitors in Thyroid Cancers
by Francesca Cuomo, Claudio Giani and Gilda Cobellis
Pharmaceutics 2022, 14(5), 1040; https://doi.org/10.3390/pharmaceutics14051040 - 11 May 2022
Cited by 9 | Viewed by 1970
Abstract
Thyroid cancer is the most common endocrine malignancy, accounting for about 3% of all cancer cases each year worldwide with increasing incidence, but with the mortality remaining stable at low levels. This contradiction is due to overdiagnosis of indolent neoplasms identified by neck [...] Read more.
Thyroid cancer is the most common endocrine malignancy, accounting for about 3% of all cancer cases each year worldwide with increasing incidence, but with the mortality remaining stable at low levels. This contradiction is due to overdiagnosis of indolent neoplasms identified by neck ultrasound screening that would remain otherwise asymptomatic. Differentiated thyroid carcinomas (DTCs) are almost curable for 95% with a good prognosis. However, 5% of these tumours worsened toward aggressive forms: large tumours with extravasal invasion, either with regional lymph node or distant metastasis, that represent a serious clinical challenge. The unveiling of the genomic landscape of these tumours shows that the most frequent mutations occur in tyrosine kinase receptors (RET), in components of the MAPK/PI3K signalling pathway (RAS and BRAF) or chromosomal rearrangements (RET/PTC and NTRK hybrids); thus, tyrosine-kinase inhibitor (TKI) treatments arose in the last decade as the most effective therapeutic option for these aggressive tumours to mitigate the MAPK/PI3K activation. In this review, we summarize the variants of malignant thyroid cancers, the molecular mechanisms and factors known to contribute to thyroid cell plasticity and the approved drugs in the clinical trials and those under investigation, providing an overview of available treatments toward a genome-driven oncology, the only opportunity to beat cancer eventually through tailoring the therapy to individual genetic alterations. However, radiotherapeutic and chemotherapeutic resistances to these anticancer treatments are common and, wherever possible, we discuss these issues. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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30 pages, 14508 KiB  
Review
Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer
by Shangwei Zhong, Shoujiao Peng, Zihua Chen, Zhikang Chen and Jun-Li Luo
Pharmaceutics 2022, 14(3), 498; https://doi.org/10.3390/pharmaceutics14030498 - 24 Feb 2022
Cited by 6 | Viewed by 4069
Abstract
Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is [...] Read more.
Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge. Accumulating evidence suggests that abnormal expression and activation of various kinases are associated with the emergence and maintenance of CRPC. Many efforts have been made to develop small molecule inhibitors to target the key kinases in CRPC. These inhibitors are designed to suppress the kinase activity or interrupt kinase-mediated signal pathways that are associated with PCa androgen-independent (AI) growth and CRPC development. In this review, we briefly summarize the roles of the kinases that are abnormally expressed and/or activated in CRPC and the recent advances in the development of small molecule inhibitors that target kinases for the treatment of CRPC. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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22 pages, 1680 KiB  
Review
BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia
by Gustavo P. Amarante-Mendes, Aamir Rana, Tarcila Santos Datoguia, Nelson Hamerschlak and Gabriela Brumatti
Pharmaceutics 2022, 14(1), 215; https://doi.org/10.3390/pharmaceutics14010215 - 17 Jan 2022
Cited by 36 | Viewed by 8223
Abstract
The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and [...] Read more.
The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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17 pages, 1409 KiB  
Review
The TKI Era in Chronic Leukemias
by Danilo De Novellis, Fabiana Cacace, Valeria Caprioli, William G. Wierda, Kris M. Mahadeo and Francesco Paolo Tambaro
Pharmaceutics 2021, 13(12), 2201; https://doi.org/10.3390/pharmaceutics13122201 - 20 Dec 2021
Cited by 11 | Viewed by 4414
Abstract
Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 [...] Read more.
Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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26 pages, 1602 KiB  
Review
Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations
by Caio Bezerra Machado, Flávia Melo Cunha de Pinho Pessoa, Emerson Lucena da Silva, Laudreísa da Costa Pantoja, Rodrigo Monteiro Ribeiro, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, Raquel Carvalho Montenegro, Rommel Mário Rodriguez Burbano, André Salim Khayat and Caroline Aquino Moreira-Nunes
Pharmaceutics 2021, 13(10), 1604; https://doi.org/10.3390/pharmaceutics13101604 - 02 Oct 2021
Cited by 4 | Viewed by 2620
Abstract
Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice [...] Read more.
Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice over the last couple decades, and in this review, we focused our discussion on relevant clinical trials of the past five years that investigated kinase inhibitor (KI) usage in patients afflicted with relapsed/refractory (R/R) hematologic malignancies as well as in the pharmacological characteristics of available KIs and the dissertation about traditional chemotherapy treatment approaches and its hindrances. A trend towards investigations on KI usage for the treatment of chronic lymphoid leukemia and acute myeloid leukemia in R/R settings was observed, and it likely reflects the existence of already established treatment protocols for chronic myeloid leukemia and acute lymphoid leukemia patient cohorts. Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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Other

9 pages, 670 KiB  
Brief Report
PKCeta Promotes Stress-Induced Autophagy and Senescence in Breast Cancer Cells, Presenting a Target for Therapy
by Noa Rotem-Dai, Amitha Muraleedharan and Etta Livneh
Pharmaceutics 2022, 14(8), 1704; https://doi.org/10.3390/pharmaceutics14081704 - 16 Aug 2022
Cited by 3 | Viewed by 1510
Abstract
The emergence of chemoresistance in neoplastic cells is one of the major obstacles in cancer therapy. Autophagy was recently reported as one of the mechanisms that promote chemoresistance in cancer cells by protecting against apoptosis and driving senescence. Thus, understanding the role of [...] Read more.
The emergence of chemoresistance in neoplastic cells is one of the major obstacles in cancer therapy. Autophagy was recently reported as one of the mechanisms that promote chemoresistance in cancer cells by protecting against apoptosis and driving senescence. Thus, understanding the role of autophagy and its underlying signaling pathways is crucial for the development of new therapeutic strategies to overcome chemoresistance. We have previously reported that PKCη is a stress-induced kinase that confers resistance in breast cancer cells against chemotherapy by inducing senescence. Here, we show that PKCη promotes autophagy induced by ER and oxidative stress and facilitates the transition from autophagy to senescence. We demonstrate that PKCη knockdown reduces both the autophagic flux and markers of senescence. Additionally, using autophagy inhibitors such as chloroquine and 3-methyladenine, we show that PKCη and autophagy are required for establishing senescence in MCF-7 in response to oxidative stress. Different drugs used in the clinic are known to induce autophagy and senescence in breast cancer cells. Our study proposes PKCη as a target for therapeutic intervention, acting in synergy with autophagy-inducing drugs to overcome resistance and enhance cell death in breast cancer. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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