Mechanism of PARP1 Elongation Reaction Revealed by Molecular Modeling.

Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the SN1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2'A-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3'A-OH group.

Real-world trends in the use of maintenance therapy in ovarian cancer across the United States from 2017 to 2021.

OBJECTIVE: We assessed real-world trends in the use of maintenance therapy [MT] (i.e., polyADP-ribose polymerase inhibitors (PARPi) and/or bevacizumab following platinum-based chemotherapy), among U.S. patients with ovarian cancer. METHODS: Using Medicare and commercial administrative health claims data from Optum's de-identified Clinformatics® Data Mart Database, we identified patients who had been diagnosed with ovarian cancer between January 1, 2010, and March 31, 2021, and received platinum-based chemotherapy and MT. Multivariable logistic regression and Cox proportional hazards regression were used to evaluate associations between demographic and clinical characteristics and MT use. RESULTS: Our study included 6339 patients, with a median age of 70 years. The majority were White (70.1 %), Medicare-insured (71.9 %), and were treated in the South (42.5 %). Of the 31.5 % who received MT, 18.1 % received bevacizumab alone, 10.2 % PARPi alone, and 3.3 % both. After adjusting for insurance type, PARPi and bevacizumab use increased significantly from 2017 to 2020. Patients with a high Elixhauser comorbidity index were more likely to receive MT than were patients with a low index [OR (95 % CI): 1.46 (1.28-1.67), p < 0.0001]. PARPi use was significantly associated with treatment in the South [1.42 (1.10-1.83), p = 0.01]. Compared to patients who received neither agents, those who received bevacizumab, alone or in combination with PARPi, had a higher risk of death [HR = 2.02 (95 % CI: 1.70-2.28, p < 0.0001) and 1.66 (1.24-2.23), p = 0.001, respectively]. CONCLUSIONS: The majority of patients with ovarian cancer are not utilizing maintenance therapy after platinum-based chemotherapy. Age, comorbidity status, and geographic region of treatment were associated with MT use. Understanding the factors and real-world outcomes associated with MT use is important to support patients in making value concordant and informed decisions.

Efficacy of a platinum-based chemotherapy rechallenge for platinum-sensitive recurrence after PARP inhibitor maintenance.

Objective: Platinum-free interval (PFI) is the period from the end of platinum-based chemotherapy to the date of recurrence. If the PFI is > 6 months, a platinum-based chemotherapy rechallenge is considered; however, its efficacy after poly adenosine 5'-diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy is unknown. This study aimed to examine the efficacy of a platinum-based chemotherapy rechallenge after PARP inhibitor therapy. Methods: We retrospectively evaluated patients with ovarian cancer with a PFI≥6 months with PARP inhibitor maintenance therapy, receiving platinum-based chemotherapy. Duration of PARP inhibitor therapy, best response to subsequent platinum chemotherapy rechallenge, and clinical characteristics were collected from medical records. Tumor response was assessed according to RECIST 1.1. Correlations were calculated using Spearman's correlation coefficients. Results: Among the 10 included patients, seven (70 %) received PARP inhibitors after primary chemotherapy, and three (30 %) received chemotherapy for platinum-sensitive relapse. One and five patients harbored a germline BRCA1 and BRCA wild-type mutations, respectively, and two had homologous recombination proficiency. The median PFI was 303.5 (182-602) days, and PARP inhibitor therapy duration was 249 (147-570) days. Platinum chemotherapy rechallenge efficacy was complete and partial response and stable disease in one (10 %), six (60 %), and three (30 %) patients, respectively. The longer the duration of PARP inhibitor treatment, better the response to platinum agents (Spearman correlation coefficient 0.284, p = 0.0288). Conclusion: Platinum-based chemotherapy rechallenge is reasonable for patients with platinum-sensitive disease, using the traditional PFI cutoff of 6 months, even when the PFI is obtained with a maintenance PARP inhibitor.

Identification of a novel DNA oxidative damage repair pathway, requiring the ubiquitination of the histone variant macroH2A1.1.

BACKGROUND: The histone variant macroH2A (mH2A), the most deviant variant, is about threefold larger than the conventional histone H2A and consists of a histone H2A-like domain fused to a large Non-Histone Region responsible for recruiting PARP-1 to chromatin. The available data suggest that the histone variant mH2A participates in the regulation of transcription, maintenance of heterochromatin, NAD+ metabolism, and double-strand DNA repair. RESULTS: Here, we describe a novel function of mH2A, namely its implication in DNA oxidative damage repair through PARP-1. The depletion of mH2A affected both repair and cell survival after the induction of oxidative lesions in DNA. PARP-1 formed a specific complex with mH2A nucleosomes in vivo. The mH2A nucleosome-associated PARP-1 is inactive. Upon oxidative damage, mH2A is ubiquitinated, PARP-1 is released from the mH2A nucleosomal complex, and is activated. The in vivo-induced ubiquitination of mH2A, in the absence of any oxidative damage, was sufficient for the release of PARP-1. However, no release of PARP-1 was observed upon treatment of the cells with either the DNA alkylating agent MMS or doxorubicin. CONCLUSIONS: Our data identify a novel pathway for the repair of DNA oxidative lesions, requiring the ubiquitination of mH2A for the release of PARP-1 from chromatin and its activation.

A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer.

BACKGROUND: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi. METHODS: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes). RESULTS: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10-7). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070). CONCLUSIONS: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation.

Association of PARP1 Expression Levels and Clinical Parameters in Different Leukemic Subtypes With BCR::ABL1 p190+ Translocation.

Background/Aim: Although the reciprocal translocation t(9;22)(q34;q11) is a hallmark of chronic myeloid leukemia (CML), it is also present in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Depending on the gene's breakpoint, it is possible to obtain three isoforms, among which p190 stands out for the poor prognosis it induces whenever it appears. Due to the genomic instability induced by BCR::ABL1, it is proposed to expand the applicability of poly-ADP-ribose polymerase-1 (PARP1) and its inhibitors in hematological neoplasms. Materials and Methods: We measured the expression levels of PARP1 by quantitative real-time PCR (qPCR) using TaqMan®, correlating its expression with BCR::ABL1 p190+, to evaluate its influence in the clinic of adult patients. Results: We found that PARP1 is expressed differently in ALL, AML and CML and that p190 transcripts do not follow a linear pattern in these populations. We also found that PARP1 expression is not correlated with age, white blood cell and the amount of p190 transcripts. Conclusion: Despite the lack of statistical correlation between the variables analyzed, the role of PARP1 in BCR::ABL1 leukemia cannot be ruled out, given the instability profile promoted by this translocation. Finally, further studies involving a larger sample of patients are needed, as well as investigations into other molecular pathways that may impact on the pathogenesis of different BCR::ABL1 leukemic subtypes.

Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors.

BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.

The Rate of NAD+ Breakdown Is Maintained Constant against Deletion or Overexpression of NAD+-Degrading Enzymes in Mammalian Cells.

Cellular NAD+ is continuously degraded and synthesized under resting conditions. In mammals, NAD+ synthesis is primarily initiated from nicotinamide (Nam) by Nam phosphoribosyltransferase, whereas poly(ADP-ribose) polymerase 1 (PARP1) and 2 (PARP2), sirtuin1 (SIRT1), CD38, and sterile alpha and TIR motif containing 1 (SARM1) are involved in NAD+ breakdown. Using flux analysis with 2H-labeled Nam, we found that when mammalian cells were cultured in the absence of Nam, cellular NAD+ levels were maintained and NAD+ breakdown was completely suppressed. In the presence of Nam, the rate of NAD+ breakdown (RB) did not significantly change upon PARP1, PARP2, SIRT1, or SARM1 deletion, whereas stable expression of CD38 did not increase RB. However, RB in PARP1-deleted cells was much higher compared with that in wild-type cells, in which PARP1 activity was blocked with a selective inhibitor. In contrast, RB in CD38-overexpressing cells in the presence of a specific CD38 inhibitor was much lower compared with that in control cells. The results indicate that PARP1 deletion upregulates the activity of other NADases, whereas CD38 expression downregulates the activity of endogenous NADases, including PARP1 and PARP2. The rate of cellular NAD+ breakdown and the resulting NAD+ concentration may be maintained at a constant level, despite changes in the NAD+-degrading enzyme expression, through the compensatory regulation of NADase activity.

Current HRD assays in ovarian cancer: differences, pitfalls, limitations, and novel approaches.

Ovarian carcinoma (OC) still represents an insidious and fatal malignancy, and few significant results have been obtained in the last two decades to improve patient survival. Novel targeted therapies such as poly (ADP-ribose) polymerase inhibitors (PARPi) have been successfully introduced in the clinical management of OC, but not all patients will benefit, and drug resistance almost inevitably occurs. The identification of patients who are likely to respond to PARPi-based therapies relies on homologous recombination deficiency (HRD) tests, as this condition is associated with response to these treatments. This review summarizes the genomic and functional HRD assays currently used in clinical practice and those under evaluation, the clinical implications of HRD testing in OC, and their current pitfalls and limitations. Special emphasis will be placed on the functional HRD assays under development and the use of machine learning and artificial intelligence technologies as novel strategies to overcome the current limitations of HRD tests for a better-personalized treatment to improve patient outcomes.

METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor.

The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

[Metastatic castration-resistant prostate cancer and PARP inhibitors: From tumor genomics to new therapeutic combinations]. / Cancer de prostate métastatique résistant à la castration et inhibiteurs de PARP : de la génomique tumorale aux nouvelles associations thérapeutiques.

Castration-resistant metastatic prostate cancer remains lethal and a therapeutic challenge. Current strategies are geared towards the personalization of treatments based on the identification of relevant molecular targets, including genomic alterations involved in tumoral processes. Among these novel targeted therapies, poly-ADP-ribose polymerase inhibitors (PARPi), by blocking the action of enzymes involved in deoxyribonucleic acid (DNA) repair, induce the destruction of cells carrying defects in homologous recombination repair, often associated with alterations in genes involved in this mechanism. Thus, determining the presence of a molecular anomaly, particularly alterations in the BRCA1/2 genes, is a prerequisite for initiating PARPi monotherapy. In patients with metastatic castration-resistant prostate cancer , around 20-30 % carry this type of mutation. In this population, single-agent studies have demonstrated PARPi ability to prolong overall survival, and to improve symptom control, including pain. Other studies are underway to assess their effectiveness in combination with other therapies, and it already appears that association with new-generation hormone therapy can further prolong radiological progression-free survival, regardless of the mutation status of the genes involved in DNA repair, indicating a synergistic action between PARPi and new-generation hormone therapy.

The CD47/TSP-1 axis: a promising avenue for ovarian cancer treatment and biomarker research.

BACKGROUND: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. METHODS: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. RESULTS: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. CONCLUSIONS: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer.

INTRODUCTION: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result. METHODS: GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record. RESULTS: Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result. CONCLUSIONS: Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

Exploring the impact of BRCA1 and BRCA2 mutation type and location on Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer patients: A single center report.

OBJECTIVE: In patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2-mutated PSROC patients, focusing on the type and location of PV. METHODS: We assessed the outcomes of 100 BRCA1/2-mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS). RESULTS: PFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects. CONCLUSIONS: In summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients. TRIAL REGISTRATION NUMBER: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015.

Application of PARP inhibitors combined with immune checkpoint inhibitors in ovarian cancer.

The advent of polyadenosine diphosphate ribose polymerase inhibitors (PARPi) has brought about significant changes in the field of ovarian cancer treatment. However, in 2022, Rucaparib, Olaparib, and Niraparib, had their marketing approval revoked for third-line and subsequent therapies due to an increased potential for adverse events. Consequently, the exploration of new treatment modalities remains imperative. Recently, the integration of PARPi with immune checkpoint inhibitors (ICIs) has emerged as a potential remedy option within the context of ovarian cancer. This article offers a comprehensive examination of the mechanisms and applications of PARPi and ICIs in the treatment of ovarian cancer. It synthesizes the existing evidence supporting their combined use and discusses key considerations that merit attention in ongoing development efforts.

Therapeutic targeting of PARP with immunotherapy in acute myeloid leukemia.

Targeting the poly (ADP-ribose) polymerase (PARP) protein has shown therapeutic efficacy in cancers with homologous recombination (HR) deficiency due to BRCA mutations. Only small fraction of acute myeloid leukemia (AML) cells carry BRCA mutations, hence the antitumor efficacy of PARP inhibitors (PARPi) against this malignancy is predicted to be limited; however, recent preclinical studies have demonstrated that PARPi monotherapy has modest efficacy in AML, while in combination with cytotoxic chemotherapy it has remarkable synergistic antitumor effects. Immunotherapy has revolutionized therapeutics in cancer treatment, and PARPi creates an ideal microenvironment for combination therapy with immunomodulatory agents by promoting tumor mutation burden. In this review, we summarize the role of PARP proteins in DNA damage response (DDR) pathways, and discuss recent preclinical studies using synthetic lethal modalities to treat AML. We also review the immunomodulatory effects of PARPi in AML preclinical models and propose future directions for therapy in AML, including combined targeting of the DDR and tumor immune microenvironment; such combination regimens will likely benefit patients with AML undergoing PARPi-mediated cancer therapy.

Regulation of PARP1/2 and the tankyrases: emerging parallels.

ADP-ribosylation is a prominent and versatile post-translational modification, which regulates a diverse set of cellular processes. Poly-ADP-ribose (PAR) is synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), and tankyrase 2 (TNKS2), all of which are linked to human disease. PARP1/2 inhibitors have entered the clinic to target cancers with deficiencies in DNA damage repair. Conversely, tankyrase inhibitors have continued to face obstacles on their way to clinical use, largely owing to our limited knowledge of their molecular impacts on tankyrase and effector pathways, and linked concerns around their tolerability. Whilst detailed structure-function studies have revealed a comprehensive picture of PARP1/2 regulation, our mechanistic understanding of the tankyrases lags behind, and thereby our appreciation of the molecular consequences of tankyrase inhibition. Despite large differences in their architecture and cellular contexts, recent structure-function work has revealed striking parallels in the regulatory principles that govern these enzymes. This includes low basal activity, activation by intra- or inter-molecular assembly, negative feedback regulation by auto-PARylation, and allosteric communication. Here we compare these poly-ADP-ribosyltransferases and point towards emerging parallels and open questions, whose pursuit will inform future drug development efforts.

Poly (ADP-ribose) polymerase inhibitor therapy and mechanisms of resistance in epithelial ovarian cancer.

Advanced epithelial ovarian cancer is the commonest cause of gynaecological cancer deaths. First-line treatment for advanced disease includes a combination of platinum-taxane chemotherapy (post-operatively or peri-operatively) and maximal debulking surgery whenever feasible. Initial response rate to chemotherapy is high (up to 80%) but most patients will develop recurrence (approximately 70-90%) and succumb to the disease. Recently, poly-ADP-ribose polymerase (PARP) inhibition (by drugs such as Olaparib, Niraparib or Rucaparib) directed synthetic lethality approach in BRCA germline mutant or platinum sensitive disease has generated real hope for patients. PARP inhibitor (PARPi) maintenance therapy can prolong survival but therapeutic response is not sustained due to intrinsic or acquired secondary resistance to PARPi therapy. Reversion of BRCA1/2 mutation can lead to clinical PARPi resistance in BRCA-germline mutated ovarian cancer. However, in the more common platinum sensitive sporadic HGSOC, the clinical mechanisms of development of PARPi resistance remains to be defined. Here we provide a comprehensive review of the current status of PARPi and the mechanisms of resistance to therapy.

Endogenous base damage as a driver of genomic instability in homologous recombination-deficient cancers.

Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to a variety of cancer types, underscoring the importance of error-free repair of DSBs in human physiology. While environmental sources of DSBs have been known, more recent studies have begun to uncover the role of endogenous base damage in leading to these breaks. Base damage repair intermediates often consist of single-strand breaks, which if left unrepaired, can lead to DSBs as the replication fork encounters these lesions. This review summarizes various sources of endogenous base damage and how these lesions are repaired. We highlight how conversion of base repair intermediates, particularly those with 5'or 3' blocked ends, to DSBs can be a predominant source of genomic instability in HR-deficient cancers. We also discuss how endogenous base damage and ensuing DSBs can be exploited to enhance the efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi), that are widely used in the clinics for the regimen of HR-deficient cancers.