scholarly journals RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer

2021 ◽  
Author(s):  
chenkui Miao ◽  
Takuya Tsujino ◽  
Tomoaki Takai ◽  
Gui Fu ◽  
Takeshi Tsutsumi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Excision Repair ◽  
Single Gene ◽  
Parp Inhibitor ◽  
Clinical Results ◽  
Parp Inhibition ◽  
Cancer Therapies ◽  
Genomic Alterations ◽  
Repair Capacity ◽  
Inhibitor Resistance

Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 re-sensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic testing to determine who may benefit from PARP inhibition. Finally, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss.

Kinase Phosphorylation-based Mechanisms of PARP Inhibitor Resistance During Synthetic Lethal Oncotherapy

2020 ◽  
Vol 15 (1) ◽  
pp. 12-23
Author(s):  
Eriko Osaki ◽  
Shinya Mizuno
Keyword(s):  
Cancer Progression ◽  
Catalytic Domain ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Clinical Importance ◽  
Parp Inhibition ◽  
Special Focus ◽  
Driver Genes ◽  
Kinase Phosphorylation

Background: Poly-(ADP-Ribose) Polymerase (PARP) plays a central role in recovery from single-strand DNA (ssDNA) damage via base excision repair. When PARP activity is inhibited by a NAD+ mimetic analog, ssDNA is converted into a Double-Strand Break (DSB) during the S-phase in a cell cycle. However, the DSB site is repaired in a process of Homologous Recombination (HR) that is derived by genes such as BRCA1/2, PALB2, and RAD51. Under conditions of HR dysfunction, including mutations of BRCA1/2 (called BRCAness), PARP inhibitor (PARPi) induces “synthetic lethality” in BRCAness-specific cancer cells. Indeed, clinical trials using forms of PARPi that include olaparib, veliparib and rucaparib, have revealed that PARP inhibition produces a dramatic effect that actually arrests cancer progression. Its clinical efficiency is limited, however, due to the acquisition of PARPi resistance during long-term use of this inhibitor. Thus, it is important to elucidate the mechanisms of PARPi resistance. Methods: We searched the scientific literature published in PubMed, with a special focus on kinase phosphorylation that is involved in acquiring PARPi resistance. We also summarized the possible molecular events for recovering HR system, a key event for acquiring PARPi resistance. Results: CDK1 is a critical kinase for 5’-3’ DNA end resection, which is important for generating ssDNA for recruiting HR-priming factors. CDK12 is necessary for the transcription of HR-driver genes, such as BRCA1, BRCA2, RAD51 and ATR via the phosphorylation of RNA Pol-II. PLK-1 participates in driving HR via the phosphorylation of RAD51. The PI3K-AKT-mTOR signaling cascade is involved in BRCA1 induction via an ETS1 transcriptional pathway. Even under ATMdeficient conditions, the ATR-CHK1 axis compensates for loss in the DNA damage response, which results in HR recovery. The HGF receptor Met tyrosine kinase is responsible for promoting DNA repair by activating the PARP catalytic domain. Conclusion: These kinase-based signaling pathways are biologically important for understanding the compensatory system of HR, whereas inactivation of these kinases has shown promise for the release of PARPi resistance. Several lines of preclinical studies have demonstrated the potential use of kinase inhibitors to enhance PARPi sensitivity. We emphasize the clinical importance of chemical inhibitors as adjuvant drugs to block critical kinase activities and prevent the possible PARPi resistance.

scholarly journals PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2054
Author(s):  
Elizabeth K. Lee ◽  
Ursula A. Matulonis
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Combination Therapies ◽  
Mechanisms Of Resistance ◽  
Damage Repair ◽  
Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5087-TPS5087 ◽  
Author(s):  
Sumit Kumar Subudhi ◽  
Ana Aparicio ◽  
Amado J. Zurita ◽  
Bernard Doger ◽  
William Kevin Kelly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Parp Inhibitor ◽  
Rapid Identification ◽  
Abiraterone Acetate ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Abstract Submission

TPS5087 Background: Assessing multiple therapies in a single clinical trial can facilitate the rapid identification of new agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib (Nirap) is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. PARP inhibition may be especially lethal in tumor cells with genetic DNA damage response deficits (DRD). Based on promising preclinical and clinical data, this study is designed as a master protocol with nirap as a backbone therapy. Combination 1 assesses the safety and efficacy of nirap plus JNJ-63723283 (JNJ-283), an anti-PD-1 monoclonal antibody. Combination 2 assesses nirap plus abiraterone acetate and prednisone (AA-P). Methods: This multicenter, global, open-label study is currently open at 18 sites in 5 countries of the planned XX sites, and is enrolling patients with mCRPC who have progressed on ≥1 androgen-receptor targeted therapy for mCRPC. Enrollment at time of abstract submission was 25 for combination 1. When combined with AA-P, the RP2D has been determined to be nirap 200 mg. The recommended phase-2 dose (RP2D) of nirap plus JNJ-283 was determined in Part 1 based on the incidence of specified adverse events and PK data to be 480 mg every 4 weeks. For Part 2 of the study, patients are assigned to receive oral niraparib daily plus JNJ-283 infusions once every four weeks until disease progression, unacceptable toxicity, death, study termination. Part 2 is described in the table. Clinical trial information: NCT03431350. [Table: see text]

scholarly journals Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

2019 ◽  
Author(s):  
Zsofia Sztupinszki ◽  
Miklos Diossy ◽  
Marcin Krzystanek ◽  
Judit Borcsok ◽  
Mark Pomerantz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Next Generation Sequencing Data ◽  
Parp Inhibition ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Homologous Recombination Deficiency ◽  
Platinum Based Chemotherapy ◽  
Inhibitor Treatment

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

scholarly journals The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1178 ◽  
Author(s):  
Megan Crumbaker ◽  
Eva K. F. Chan ◽  
Tingting Gong ◽  
Niall Corcoran ◽  
Weerachai Jaratlerdsiri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Precision Medicine ◽  
Metastatic Prostate Cancer ◽  
Parp Inhibitor ◽  
Locally Advanced ◽  
Genomic Data ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Therapeutic Decision Making ◽  
The Impact

Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to individualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients; whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour samples were derived from prostate, lymph nodes, bone and brain. Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in individual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an individual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an individual at any stage of the disease.

Randomized phase II study of 2nd-line FOLFIRI versus modified FOLFIRI with PARP inhibitor ABT-888 (veliparib) (NSC-737664) in metastatic pancreatic cancer (mPC): SWOG S1513.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4147-TPS4147
Author(s):  
E. Gabriela Chiorean ◽  
Shannon McDonough ◽  
Philip Agop Philip ◽  
Elizabeth M. Swisher ◽  
Michael J. Pishvaian ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Parp Inhibitor ◽  
New Drugs ◽  
Parp Inhibition ◽  
Dna Breaks ◽  
Antitumor Effects ◽  
Repair Capacity ◽  
Randomized Phase Ii

TPS4147 Background: PC is characterized by multiple DNA repair defects, including in BRCA1/ 2, and other homologous recombination (HR) genes such as FANC, ATM, ATR (Waddell N, Nature 2015). Folinic acid/5-fluorouracil/ irinotecan (FOLFIRI) is a 2nd line therapy option in mPC, but overall survival (OS) averages only 6 mos (Yoo C, Br J Cancer 2009). It is known that PARP facilitates repair from topoisomerase 1-associated DNA damage, and that preclinically PARP inhibitors (PARPi) increase DNA breaks from camptothecins, resulting in synergistic antitumor effects (Smith LM, Clin Cancer Res 2005, Davidson D, Invest New Drugs 2013). PARPi are active in mPC harboring BRCA1/2 mutations. Given the preclinical synergism between ABT-888 with irinotecan, and the safety and preliminary efficacy noted in a phase I trial (Berlin J, J Clin Oncol 2014; abstr 2574), we designed a randomized phase II study of mFOLFIRI /ABT-888 vs FOLFIRI alone for 2nd line mPC patients (pts). Blood and tumor samples are collected at baseline to retrospectively analyze biomarkers related to DNA repair capacity, including the HRD assay and BROCA-HR, a targeted multi-gene sequencing to detect alterations within the Fanconi Anemia-BRCA (HR), non-homologous end joining (NHEJ), and DNA mismatch repair pathways, and correlate with efficacy. Methods: Phase II study in 143 pts randomized (1:1) to mFOLFIRI/ABT-888 or FOLFIRI. For optimal PARP inhibition, ABT-888 is dosed Days (D) 1-7 and mFOLFIRI (no 5-FU bolus) D3-5 in 14D-cycles. In the control arm, FOLFIRI is dosed D1-3 in 14D-cycles. Primary endpoint: compare OS between treatment arms; secondary endpoints: safety, progression-free survival, response rates; translational: correlate germline/somatic BRCA1/2 mutations, and other DNA repair biomarkers with efficacy in each arm. Standard eligibility criteria apply. Assuming that the addition of ABT-888 will increase OS from 6 to 9 mos, 128 eligible pts (143 pts total) are required, based on a one-sided type 1 error of 10%, and 80% power. Kaplan-Meier methodology will be used to estimate median OS for each treatment arm. This study is open to accrual (NCT02890355). Clinical trial information: NCT02890355.

Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5097-TPS5097
Author(s):  
Saro Kasparian ◽  
Leanne Burnham ◽  
Rick Kittles ◽  
Zj Sun ◽  
Fornati Bedell ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Unmet Need ◽  
Cag Repeats ◽  
Parp Inhibition ◽  
Castration Resistance ◽  
Cellular Mechanisms

TPS5097 Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate >70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.

scholarly journals Targeted DNA Damage Repair CRISPR/Cas9 Knockout Screen Identifies Novel Classification of Poly-ADP Ribose Polymerase Inhibitors Based on Key Base Excision Repair Proteins

2020 ◽  
Author(s):  
Gregory A. Breuer ◽  
Jonathan Bezney ◽  
Nathan R. Fons ◽  
Ranjini K. Sundaram ◽  
Wanjuan Feng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Parp Inhibition ◽  
Brca1 And Brca2 ◽  
Damage Repair ◽  
Base Excision

ABSTRACTDNA repair deficiencies have become an increasingly promising target for novel therapeutics within the realm of clinical oncology. Recently, a number of inhibitors of Poly(ADP-ribose) Polymerases (PARPs) have received approval for the treatment of ovarian cancers with and without deleterious mutations in the homologous recombination proteins BRCA1 and BRCA2. Unfortunately, as over a hundred clinical trials are actively underway testing the utility of PARP inhibition across dozens of unique cancers, the mechanism of action for such inhibitors remains unclear. While many believe PARP trapping to be the most important determinant driving the cytotoxicity found in such inhibitors, clinically effective inhibitors exist which possess both strong and weak PARP-trapping qualities. Such results indicate that characterization of inhibitors as strong and weak trappers does not properly capture the intra-class characteristics of such small molecule inhibitors. Using a novel, targeted DNA damage repair and response (DDR) CRISPR/Cas9 screening library, we describe a new classification scheme for PARP inhibitors that revolves around sensitivity to key modulators of the base excision repair (BER) pathway, unrelated to trapping ability or catalytic inhibition of PARP. These findings demonstrate that inhibition of PARylation and induction of PARP trapping are not the only factors responsible for the clinical response of DDR-deficient cancers to PARP inhibition, and provide insight into the optimal choice of PARP inhibitor to be used in the setting of additional DNA repair deficiencies.

scholarly journals Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma

2020 ◽  
Author(s):  
Ksenija Nesic ◽  
Olga Kondrashova ◽  
Rachel M. Hurley ◽  
Cordelia McGehee ◽  
Cassandra J Vandenberg ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Promoter Methylation ◽  
Single Gene ◽  
Parp Inhibitor ◽  
Predictive Biomarker ◽  
Gene Copy ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Gene Copies ◽  
Inhibitor Resistance

ABSTRACTWhile loss of BRCA1 promoter methylation has been shown to cause PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSC), the impacts of RAD51C methylation (meRAD51C) remain unresolved. In this study, three PARPi-responsive HGSC patient-derived xenografts (PDX) with RAD51C gene silencing and homologous recombination deficiency were found to have either homogeneous or heterogeneous patterns of meRAD51C. PDX could lose meRAD51C following PARPi treatment (rucaparib/niraparib), where a single unmethylated RAD51C copy was sufficient to drive PARPi-resistance. Genomic profiling revealed this resistance was acquired independently in two distinct PDX lineages. Furthermore, we describe a patient sample where 1/3 RAD51C gene copies lost methylation following neoadjuvant chemotherapy. We show meRAD51C is a positive predictive biomarker for PARPi response and should be screened for routinely in patients. However, methylation loss in a single gene copy is sufficient to cause PARPi resistance and should be carefully assessed in previously treated patients considering PARPi therapy.

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