Identifying and Overcoming Mechanisms of PARP Inhibitor Resistance in Homologous Recombination Repair-Deficient and Repair-Proficient High Grade Serous Ovarian Cancer Cells

Abstract

High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib.

Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers

“…Loss of PARG in BRCA2-deficient cells that are being treated with a PARPi is thought to lead to partial restoration of PARylation so that there is decreased PARP trapping and also some return of DNA-damage repair signaling, ultimately leading to PARPi resistance [123] . Studies conducted to assess mechanisms of resistance to PARPi in ovarian cancer cells detected reduced PARG levels in both HR-proficient and HR-deficient cell lines [124] , supporting the notion that loss of PARG can contribute to the development of PARPi drug resistance. Interestingly, in cells that have not been previously treated with PARPi, inhibition of PARG appears to be synthetically lethal with HR deficiency [125] , restoring PARPi sensitivity.…”

“…WEE1 kinase functions to prolong the G2 phase of the cell cycle by phosphorylating CDK1, thus inhibiting it and preventing it from initiating progression of the cell cycle while cells repair DNA damages. One study showed that both HR-deficient and HR-proficient high-grade serous ovarian cancer cells with resistance to olaparib were sensitive to treatment with WEE1 kinase inhibitor, AZD1775 [124] . It is thought that WEE1 inhibitors promote more DNA damage and thus cell death in the absence of inhibitor CDK1 phosphorylation.…”

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

“…PARP inhibitors are now used as a maintenance therapy for patients with BRCA MUT epithelial ovarian cancer and as a treatment of relapsed BRCA MUT ovarian cancer in patients who have been treated with two or more chemotherapies before [ 32 , 33 ]. Despite their effectiveness, resistance to PARP inhibitors has been clinically reported [ 34 , 35 , 36 ]. Thus, it is critical to determine the mechanism of action of PARPi, as well as other inhibitors that compromise genomic stability linked to cell cycle disruption.…”

Germline PALB2 Variants and PARP Inhibitors in Endometrial Cancer

“…15,16 In high-grade serous ovarian carcinomas, some authors have suggested that one of the PARP inhibitor resistance mechanisms may be reduction in levels of poly(ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. 17 Whether similar mechanisms of resistance are in action in the setting of PARP inhibition for PALB2-mutated cancers requires further investigation. Understanding the mechanisms of resistance will also help to inform the utility, if any, of switching between PARP inhibitors at progression, an issue for which there are currently limited data.…”