BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.

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The Role of PARP Inhibitors in the Treatment of Prostate Cancer: Recent Advances in Clinical Trials

Biomolecules ◽

10.3390/biom11050722 ◽

2021 ◽

Vol 11 (5) ◽

pp. 722

Author(s):

Mingyue Xia ◽

Zhigang Guo ◽

Zhigang Hu

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Synthetic Lethality ◽

Adenosine Diphosphate ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Castration Resistant Prostate Cancer ◽

Brca Mutations ◽

Combination Treatments ◽

Bet Inhibitors

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) belong to a class of targeted drugs developed for the treatment of homologous recombination repair (HRR)-defective tumors. Preclinical and limited clinical data suggest that PARP inhibition is effective against prostate cancer (PC) in patients with HRR-deficient tumors and that PARPis can improve the mortality rate of PC in patients with BRCA1/2 mutations through a synthetic lethality. Olaparib has been approved by the FDA for advanced ovarian and breast cancer with BRCA mutations, and as a maintenance therapy for ovarian cancer after platinum chemotherapy. PARPis are also a new and emerging clinical treatment for metastatic castration-resistant prostate cancer (mCRPC). Although PARPis have shown great efficacy, their widespread use is restricted by various factors, including drug resistance and the limited population who benefit from treatment. It is necessary to study the combination of PARPis and other therapeutic agents such as anti-hormone drugs, USP7 inhibitors, BET inhibitors, and immunotherapy. This article reviews the mechanism of PARP inhibition in the treatment of PC, the progress of clinical research, the mechanisms of drug resistance, and the strategies of combination treatments.

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Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects

Case Medical Research ◽

10.31525/ct1-nct04030559 ◽

2019 ◽

Author(s):

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

High Risk ◽

Dna Damage Response ◽

Localized Prostate Cancer ◽

Damage Response

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Abstract 2362: Long non-coding RNA NORAD interaction with miR-346 impacts DNA damage response and anti-tumor immunity in prostate cancer

10.1158/1538-7445.am2021-2362 ◽

2021 ◽

Author(s):

Claire Fletcher ◽

Lin Deng ◽

Folake Orafidiya ◽

Wei Yuan ◽

Ines Figueiredo ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Tumor Immunity ◽

Non Coding Rna ◽

Damage Response ◽

Long Non Coding Rna

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NKX3.1 contributes to S phase entry and regulates DNA damage response (DDR) in prostate cancer cell lines

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2011.09.035 ◽

2011 ◽

Vol 414 (1) ◽

pp. 123-128 ◽

Cited By ~ 8

Author(s):

Burcu Erbaykent-Tepedelen ◽

Besra Özmen ◽

Lokman Varisli ◽

Ceren Gonen-Korkmaz ◽

Bilge Debelec-Butuner ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Cell Lines ◽

Cancer Cell ◽

Dna Damage Response ◽

Prostate Cancer Cell ◽

S Phase ◽

Prostate Cancer Cell Lines ◽

Damage Response ◽

Phase Entry

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A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

Scientific Reports ◽

10.1038/s41598-021-93715-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lorena Magraner-Pardo ◽

Roman A. Laskowski ◽

Tirso Pons ◽

Janet M. Thornton

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Protein Interaction ◽

Three Dimensional ◽

Protein Protein Interaction ◽

Variants Of Unknown Significance ◽

Damage Response ◽

Dna Variants ◽

Unknown Significance

AbstractDNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

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A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽

10.1515/folmed-2017-0067 ◽

2018 ◽

Vol 60 (1) ◽

pp. 39-47 ◽

Cited By ~ 8

Author(s):

Ashish P. Shah ◽

Chhagan N. Patel ◽

Dipen K. Sureja ◽

Kirtan P. Sanghavi

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Therapy ◽

Repair Process ◽

Parp Inhibitors ◽

Brca Mutations ◽

Development Of Resistance ◽

Damage Repair ◽

Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

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Phase II trial of the PARP inhibitor, niraparib, in BRCA1-Associated Protein 1 (BAP1) and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps354 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS354-TPS354

Author(s):

Thomas J. George ◽

David L. DeRemer ◽

Ji-Hyun Lee ◽

Stephen Staal ◽

Merry Jennifer Markham ◽

...

Keyword(s):

Dna Damage ◽

Solid Tumors ◽

Dna Damage Response ◽

Group Performance ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Mutant Cell ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Damage Response

TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]

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