Anti-cancer immune responses to DNA damage response inhibitors: Molecular mechanisms and progress toward clinical translation

Carlsen, Lindsey; El‐Deiry, Wafik S.

doi:10.3389/fonc.2022.998388

Cited by 19 publications

(7 citation statements)

References 112 publications

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“…3A ). PARP inhibitors kill tumor cells primarily through the induction of DNA DSBs [ 19 ]. Thus, we evaluated olaparib-induced formation of γH2AX, which is H2AX phosphorylated at the S139 site and is recognized as the biomarker for DNA DSBs, in cells expressing control or Rictor shRNA.…”

Section: Resultsmentioning

confidence: 99%

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

Bu¹,

Zhao²,

Wang³

et al. 2023

Oncology Research

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Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months, and conventional chemotherapeutics are the main treatment strategy. Poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer, opening a new era for targeted therapy for this disease. However, most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to PARP inhibitors. Here, we reported that mammalian target of rapamycin complex 2 (mTORC2) kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and invasion. Moreover, we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the PARP inhibitor olaparib. Mechanistically, we showed that mTORC2 positively regulates homologous recombination (HR) repair by modulating BRCA1 recruitment to DNA double-strand breaks (DSBs). In addition, we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo . Thus, this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.

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Section: Resultsmentioning

confidence: 99%

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

Bu¹,

Zhao²,

Wang³

et al. 2023

Oncology Research

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“…However, TOPII inhibitors create DNA adducts, inter-strand crosslinks, and ROSinduced DNA damage, with some evidence reporting the involvement of alternative repair pathways in removing chemotherapeutic drug damage [163][164][165][166][167]. Notably, tyrosyl-DNA phosphodiesterase plays a crucial role in reconnecting and regenerating damaged DNA fragments, forming a covalent intermediate with a tyrosine residue.…”

Section: Dna Damage Response Pathways and Topo-active Drug Resistancementioning

confidence: 99%

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Sharma,

Bahot,

Sekar

et al. 2024

Cancers

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In recent years, the emergence of cancer drug resistance has been one of the crucial tumor hallmarks that are supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters, and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often result in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores the use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

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“…So far, our discussion about carboplatin resistance has focused on cell autonomous mechanisms. However, multiple pre-clinical mechanistic studies in a variety of malignancies (including HGSOC) have established the presence of DNA damage-induced innate and adaptive immune activation [ 96 – 99 ]. This necessarily implicates crosstalk between iTME in responsiveness and resistance to DNA damaging therapeutic agents [ 54 , 100 – 102 ].…”

Section: Carboplatin Resistancementioning

confidence: 99%

Multiparameter single-cell proteomic technologies give new insights into the biology of ovarian tumors

et al. 2023

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High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. Its diagnosis at advanced stage compounded with its excessive genomic and cellular heterogeneity make curative treatment challenging. Two critical therapeutic challenges to overcome are carboplatin resistance and lack of response to immunotherapy. Carboplatin resistance results from diverse cell autonomous mechanisms which operate in different combinations within and across tumors. The lack of response to immunotherapy is highly likely to be related to an immunosuppressive HGSOC tumor microenvironment which overrides any clinical benefit. Results from a number of studies, mainly using transcriptomics, indicate that the immune tumor microenvironment (iTME) plays a role in carboplatin response. However, in patients receiving treatment, the exact mechanistic details are unclear. During the past decade, multiplex single-cell proteomic technologies have come to the forefront of biomedical research. Mass cytometry or cytometry by time-of-flight, measures up to 60 parameters in single cells that are in suspension. Multiplex cellular imaging technologies allow simultaneous measurement of up to 60 proteins in single cells with spatial resolution and interrogation of cell–cell interactions. This review suggests that functional interplay between cell autonomous responses to carboplatin and the HGSOC immune tumor microenvironment could be clarified through the application of multiplex single-cell proteomic technologies. We conclude that for better clinical care, multiplex single-cell proteomic technologies could be an integral component of multimodal biomarker development that also includes genomics and radiomics. Collection of matched samples from patients before and on treatment will be critical to the success of these efforts.

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Anti-cancer immune responses to DNA damage response inhibitors: Molecular mechanisms and progress toward clinical translation

Cited by 19 publications

References 112 publications

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Multiparameter single-cell proteomic technologies give new insights into the biology of ovarian tumors

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