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Review
. 2023 Mar 1:15:17588359231157644.
doi: 10.1177/17588359231157644. eCollection 2023.

Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer

Ana C Veneziani  1 , Clare Scott  2   3   4   5 , Matthew J Wakefield  2 , Anna V Tinker  6 , Stephanie Lheureux  7
Affiliations
Review

Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer

Ana C Veneziani et al. Ther Adv Med Oncol. .

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a therapeutic milestone in the management of epithelial ovarian cancer. The concept of 'synthetic lethality' is exploited by PARPi in tumors with defects in DNA repair pathways, particularly homologous recombination deficiency. The use of PARPis has been increasing since its approval as maintenance therapy, particularly in the first-line setting. Therefore, resistance to PARPi is an emerging issue in clinical practice. It brings an urgent need to elucidate and identify the mechanisms of PARPi resistance. Ongoing studies address this challenge and investigate potential therapeutic strategies to prevent, overcome, or re-sensitize tumor cells to PARPi. This review aims to summarize the mechanisms of resistance to PARPi, discuss emerging strategies to treat patients post-PARPi progression, and discuss potential biomarkers of resistance.

Keywords: PARP inhibitor; biomarkers; homologous recombination deficiency; ovarian cancer; replication stress.

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Conflict of interest statement

Ana C. Veneziani and Matthew J. Wakefield declare no conflicts of interest. Stephanie Lheureux received honoraria from GSK, AstraZeneca, Merck, Eisai, Roche, and Novartis. She received grant support from GSK, Astra-Zeneca, and Roche. She is the principal investigator and co-investigator of different industry and investigational studies involved with PARP inhibitors (Astra-Zeneca, Clovis, GSK, Repare Therapeutics). Clare Scott reports non-financial support from Clovis Oncology, grants and other support from Eisai Inc, AstraZeneca, Sierra Oncology, MSD, grants from Boehringer Ingelheim, other support from Roche, Takeda, and non-financial support from Beigene. She is the principal investigator and co-investigator of clinical trials involving PARP inhibitors (Clovis Oncology and AstraZeneca). Anna Tinker received honoraria from GSK, AstraZeneca, Merck, and Eisai. She received grant support from Astra-Zeneca.

Figures

Figure 1.
Figure 1.
Mechanisms of resistance to PARPi. (a) The most common is the restoration of HR genes such as BRCA and RAD51. (b) Alterations in drug efflux pumps and the tumor microenvironment impair drug delivery leading to resistance. (c) Some signal transduction pathways promote HR and evasion of apoptosis. (d) Stabilization of replication fork allows DNA repair and fork restart. Created with BioRender.com. HR, homologous recombination; PARPi, poly (ADP-ribose) polymerase inhibitor.
Figure 2.
Figure 2.
Overcoming resistance to PARP inhibitors. Various drug (blue boxes) combination strategies have been suggested to overcome or prevent PARPi resistance, promoting replication stress, genomic instability, and cell death. (a) Immune checkpoint inhibitors, such as anti-PD-1/PD-L1, might be an alternative approach given that HR-deficient tumors usually have high levels of genomic instability and are thought to present an increased number of neoantigens on their surfaces. (b) Reactivation of the HR pathway in tumors with acquired resistance to PARP inhibitors might be counteracted by various tyrosine kinase inhibitors (such as VEGF-targeted therapies) or agents targeting epigenetic regulators of HR-related genes (such as BET domain inhibitors). (c) Cancer cells depend on replication stress response for survival. This vulnerability can be targeted by inhibiting kinases (e.g. ATR, CHK1, WEE1, PKMYT1) that coordinate the DDR with cell-cycle control. (d) PARPis impair fork progression through PARP1 trapping and inhibition of the BER. POLQ inhibitors and DNA-PK inhibitors directly inhibit MMEJ and NHEJ. Platinum agents cause inter- and intra-strand crosslinks which increase DNA damage and impair fork progression. Created with BioRender.com. BER, base excision repair; BET, bromodomain and extra-terminal; DDR, DNA damage repair; HR, homologous recombination; PARP, poly (ADP-ribose) polymerase inhibitor; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; MMEJ, microhomology-mediated end joining; NHEJ, non-homologous end joining.
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