Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

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PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽

10.3390/diagnostics9020055 ◽

2019 ◽

Vol 9 (2) ◽

pp. 55 ◽

Cited By ~ 16

Author(s):

Boussios ◽

Karathanasi ◽

Cooke ◽

Neille ◽

Sadauskaite ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Current Evidence ◽

Repair Pathway ◽

Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

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Pan-cancer analysis of non-oncogene addiction to DNA repair

10.21203/rs.3.rs-846744/v1 ◽

2021 ◽

Author(s):

Luis Bermúdez-Guzmán

Keyword(s):

Overall Survival ◽

Dna Repair ◽

Cancer Cells ◽

Synthetic Lethality ◽

The Cancer Genome Atlas ◽

Molecular Signature ◽

Systematic Evaluation ◽

Oncogene Addiction ◽

Poor Overall Survival ◽

Pan Cancer

Abstract Cancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. While we know that different cancer types can become dependent on specific DDR genes for their survival, a systematic evaluation of DNA repair addiction at the pan-cancer level is missing. In the present study, this systematic evaluation was addressed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). Following this approach, 59 DDR genes were identified as commonly essential in cancer cells with 14 genes being exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival, supporting the presence and relevance of non-oncogenic addiction to DNA repair in cancer. Particularly, UBE2T, RFC4, POLQ, BRIP1, and H2AFX represent the best predictors of poor overall survival, and some might represent promising therapeutic targets, especially under the synthetic lethality approach.

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BET Proteins as Attractive Targets for Cancer Therapeutics

International Journal of Molecular Sciences ◽

10.3390/ijms222011102 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11102

Author(s):

Joanna Sarnik ◽

Tomasz Popławski ◽

Paulina Tokarz

Keyword(s):

Homologous Recombination ◽

Transcriptional Control ◽

Synthetic Lethality ◽

Clinical Success ◽

Predictive Biomarkers ◽

Cancer Therapeutics ◽

Parp Inhibitors ◽

Novel Approach ◽

Bet Inhibitors ◽

Recombination Pathway

Transcriptional dysregulation is a hallmark of cancer and can be an essential driver of cancer initiation and progression. Loss of transcriptional control can cause cancer cells to become dependent on certain regulators of gene expression. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate the expression of multiple genes involved in carcinogenesis. BET inhibitors (BETis) disrupt BET protein binding to acetylated lysine residues of chromatin and suppress the transcription of various genes, including oncogenic transcription factors. Phase I and II clinical trials demonstrated BETis’ potential as anticancer drugs against solid tumours and haematological malignancies; however, their clinical success was limited as monotherapies. Emerging treatment-associated toxicities, drug resistance and a lack of predictive biomarkers limited BETis’ clinical progress. The preclinical evaluation demonstrated that BETis synergised with different classes of compounds, including DNA repair inhibitors, thus supporting further clinical development of BETis. The combination of BET and PARP inhibitors triggered synthetic lethality in cells with proficient homologous recombination. Mechanistic studies revealed that BETis targeted multiple essential homologous recombination pathway proteins, including RAD51, BRCA1 and CtIP. The exact mechanism of BETis’ anticancer action remains poorly understood; nevertheless, these agents provide a novel approach to epigenome and transcriptome anticancer therapy.

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Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms20123100 ◽

2019 ◽

Vol 20 (12) ◽

pp. 3100 ◽

Cited By ~ 8

Author(s):

Daniela Criscuolo ◽

Francesco Morra ◽

Riccardo Giannella ◽

Aniello Cerrato ◽

Angela Celetti

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

Androgen Deprivation ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Novel Biomarkers

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

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Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00557-3 ◽

2021 ◽

Vol 53 (1) ◽

pp. 42-51

Author(s):

Dae-Seok Kim ◽

Cristel V. Camacho ◽

W. Lee Kraus

Keyword(s):

Clinical Trials ◽

Homologous Recombination ◽

Cancer Cells ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Cancer Therapeutics ◽

Progression Free Survival ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Combination Strategies

AbstractHomologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.

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Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review

Diagnostics ◽

10.3390/diagnostics9030087 ◽

2019 ◽

Vol 9 (3) ◽

pp. 87 ◽

Cited By ~ 24

Author(s):

Stergios Boussios ◽

Peeter Karihtala ◽

Michele Moschetta ◽

Afroditi Karathanasi ◽

Agne Sadauskaite ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Synthetic Lethality ◽

Excision Repair ◽

Parp Inhibitor ◽

Advanced Ovarian Cancer ◽

Pegylated Liposomal Doxorubicin ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Biologic Agent

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

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The DNA Damaging Revolution: PARP Inhibitors and Beyond

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_238473 ◽

2019 ◽

pp. 185-195 ◽

Cited By ~ 46

Author(s):

Timothy A. Yap ◽

Ruth Plummer ◽

Nilofer S. Azad ◽

Thomas Helleday

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Therapeutic Benefit ◽

Cytotoxic Agents ◽

Parp Inhibition ◽

Breast Cancers ◽

Trial Testing

Cancer-specific DNA repair defects are abundant in malignant tissue and present an opportunity to capitalize on these aberrations for therapeutic benefit. Early preclinical data demonstrated the concept of synthetic lethality between BRCA genetic defects and pharmacologic PARP inhibition, suggesting that there may be monotherapy activity with this class of agents and supporting the early trial testing of this molecularly driven approach. Although the first foray into the clinic for PARP inhibitors was in combination with DNA-damaging cytotoxic agents, clinical development was limited by the more-than-additive toxicity, in particular dose-limiting myelosuppression. As more tolerable single agents, PARP inhibitors are now approved for the treatment of ovarian cancer in different settings and BRCA-mutant breast cancers. Beyond PARP inhibitors, there is now a large armamentarium of potent and relatively selective inhibitors in clinical trial testing against key targets involved in the DNA damage response (DDR), including ATR, ATM, CHK1/2, WEE1, and DNA-PK. These agents are being developed for patients with molecularly selected tumors and in rational combinations with other molecularly targeted agents and immune checkpoint inhibitors. We detail the clinical progress made in the development of PARP inhibitors, review rational combinations, and discuss the development of emerging inhibitors against novel DDR targets, including DNA repair proteins, DNA damage signaling, and DNA metabolism.

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Efficacy of PARP Inhibitors in the Treatment of Ovarian Cancer: A Literature-Based Review

Asian Journal of Oncology ◽

10.1055/s-0039-1700619 ◽

2019 ◽

Vol 05 (01) ◽

pp. 01-18

Author(s):

Vikas Goswami ◽

Venkata Pradeep Babu Koyyala ◽

Sumit Goyal ◽

Manish Sharma ◽

Varun Goel ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Germ Line ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Repair Mechanism ◽

Selection Of

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are a unique class of therapeutic agents that focus on tumors with deficiencies in the homologous recombination DNA repair mechanism. Genomic instability outlines high-grade serous ovarian cancer, with 50% of all tumors displaying defects in the important DNA repair mechanism of homologous recombination. Earlier research studies have demonstrated considerable efficiency for PARP inhibitors in patients with germ line breast-related cancer antigens 1 and 2 (BRCA-1/BRCA-2) mutations. It has also been observed that BRCA wild-type patients with other defects in the homologous recombination repair mechanism get benefited from this therapy. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The selection of PARP inhibitor is mainly dependent upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of cases which are most likely to get benefited from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The purpose of this review is to focus and describe the current evidences for PARP inhibitors in ovarian malignancy, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolving resistance.

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PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Cancers ◽

10.3390/cancers13184520 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4520

Author(s):

Wei Yen Chan ◽

Lauren J. Brown ◽

Lee Reid ◽

Anthony M. Joshua

Keyword(s):

Homologous Recombination ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Brca Mutations ◽

Immune Priming ◽

Combination Strategies ◽

Damage Repair

Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

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The utility of homologous recombination deficiency biomarkers across cancer types

10.1101/2021.02.18.21251882 ◽

2021 ◽

Author(s):

Shiro Takamatsu ◽

J.B. Brown ◽

Ken Yamaguchi ◽

Junzo Hamanishi ◽

Koji Yamanoi ◽

...

Keyword(s):

Homologous Recombination ◽

Cancer Cell Line ◽

Parp Inhibitors ◽

The Cancer Genome Atlas ◽

Clinical Samples ◽

Repair Deficiency ◽

Dna Repair Deficiency ◽

Cancer Genome Atlas ◽

Cancer Types ◽

Recombination Pathway

AbstractBackgroundGenomic alterations in BRCA1/2 and genomic scar signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair-related genes or other cancer types is not fully understood.ResultsWe analyzed the datasets of all solid cancers from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and found that the association between biallelic alterations in the homologous recombination pathway genes and genomic scar signatures differed greatly depending on gender and the presence of somatic TP53 mutation. Additionally, HRD cases identified by a combination of these indicators showed higher sensitivity to DNA-damaging drugs than non-HRD cases both in clinical samples and cell lines.ConclusionOur work provides novel proof of the utility of HRD analysis for all cancer types and will improve the precision and efficacy of chemotherapy selection in clinical oncology.

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