scholarly journals BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Shaolu Zhang ◽  
Xin Peng ◽  
Xiaofei Li ◽  
Hongyan Liu ◽  
Baoquan Zhao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Xenograft Model ◽  
Parp Inhibitors ◽  
Model Combination ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model ◽  
Promising Therapeutic Approach

AbstractPARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of “synthetic lethality”. However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.

scholarly journals PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

2020 ◽  
Vol 21 (21) ◽  
pp. 8288
Author(s):  
Valentina Perini ◽  
Michelle Schacke ◽  
Pablo Liddle ◽  
Salomé Vilchez-Larrea ◽  
Deborah J. Keszenman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Genotoxic Stress ◽  
Vero Cells ◽  
Limiting Factor ◽  
Parp Activation ◽  
Alternative Hypotheses

Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.

scholarly journals Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

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.

Preclinical evaluation of PARP inhibitors in combination with DNA-damaging agents in a Ewing sarcoma orthotopic xenograft model.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 10073-10073
Author(s):  
Elizabeth Stewart ◽  
David Ross Goshorn ◽  
Michael A. Dyer ◽  
Anang Shelat ◽  
Cori Bradley ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Xenograft Model ◽  
Parp Inhibitors ◽  
Preclinical Evaluation ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model ◽  
Dna Damaging Agents

scholarly journals Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations)

2021 ◽  
pp. 1432-1442
Author(s):  
Haider Mahdi ◽  
Navid Hafez ◽  
Deborah Doroshow ◽  
Davendra Sohal ◽  
Vickie Keedy ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Complete Response ◽  
Parp Inhibitors ◽  
Entire Cohort ◽  
Damage Response ◽  
Orally Bioavailable

PURPOSE Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination–directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA-mutated PARP inhibitor–resistant high-grade serous ovarian cancer (HGSOC). PATIENTS AND METHODS Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks). RESULTS Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor–resistant HGSOC, one achieved PR (–90%) and five had SD ranging 16-72 weeks (CBR 86%). CONCLUSION Olaparib with ceralasertib demonstrated preliminary activity in ATM-mutated tumors and in PARP inhibitor–resistant BRCA1/2–mutated HGSOC. These data warrant additional studies to further confirm activity in these settings.

In silico discovery of novel flavonoids as poly ADP ribose polymerase (PARP) inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Ashish Shah ◽  
Ghanshyam Parmar ◽  
Avinash Kumar Seth
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Docking Studies ◽  
Docking Score ◽  
Docking Method ◽  
Anti Cancer ◽  
In Silico Toxicity

Background: The concept of synthetic lethality is emerging field in the treatment of cancer and can be applied for new drug development of cancer as it has been already represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. Objectives: In this study we performed virtual screening of 329 flavonoids obtained from Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database to identify novel PARP inhibitors. Materials and methods: Virtual screening carried out using different In Silico methods which includes molecular docking studies, prediction of druglikeness and In Silico toxicity studies. Results: Fifteen out of 329 flavonoids achieved better docking score as compared to rucaparib which is an FDA approved PARP inhibitor. These 15 hits were again rescored using accurate docking mode and drug-likeliness properties were evaluated. Accuracy of docking method was checked using re-docking. Finally NPACT00183 and NPACT00280 were identified as potential PARP inhibitors with docking score of -139.237 and -129.36 respectively. These two flavonoids were also showed no AMES toxicity and no carcinogenicity which was predicted using admetSAR. Conclusion: Our finding suggests that NPACT00183 and NPACT00280 have promising potential to be further explored as PARP inhibitors.

scholarly journals Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Stephen Murata ◽  
Catherine Zhang ◽  
Nathan Finch ◽  
Kevin Zhang ◽  
Loredana Campo ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Damage Repair ◽  
Trial Testing ◽  
United States Food ◽  
States Food ◽  
And Personalized Medicine ◽  
Inhibitor Treatment

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use inBRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents inBRCAand non-BRCA-mutated cancers.

scholarly journals The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin

2022 ◽  
Author(s):  
Dragomir B. Krastev ◽  
Shudong Li ◽  
Yilun Sun ◽  
Andrew J. Wicks ◽  
Gwendoline Hoslett ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Homologous Recombination ◽  
Ubiquitin Ligase ◽  
Antitumour Activity ◽  
Parp Inhibitor ◽  
Bound State ◽  
Parp Inhibitors ◽  
Tumour Cells ◽  
Wild Type ◽  
Endogenous Proteins

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.

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