Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options

Abstract

Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5 years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair (HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.

Fig. 1

Mechanisms of DDR. SSB and DSB are introduced in genome in response to external or internal stimuli. A BER is the major pathway for the repair of SSB. It involves recognition of SSB and the recruitment of PARP enzymes at the DNA damage site. PARylation is initiated by the transfer of ADP-ribose residues from NAD+ to PARP, relaxes chromatin. DNA polymerase and DNA ligase III are recruited to repair DNA damage. PARP inhibitors promote ‘PARP trapping’ by blocking PARylation and preventing dissociation of PARP from the SSB site. Unrepaired SSB is converted to DSB. b HRR is the predominant pathway for DSB repair in normal cells. The DSB are sensed by the MRN complex, which activate HRR by recruiting various effector proteins such as ATM, BRCA1, BRCA2, RAD51, and FANCD. It is a high-fidelity error-free system as it uses sister chromatids as a template. NHEJ is a secondary pathway that is less active in normal cells and is error prone. c In the HRD state, NHEJ becomes the more predominant pathway, and DNA damage is accumulated during the repair process, leading to genomic instability. BER base excision repair, DDR DNA damage repair, DSB double-stranded breaks, HRD homologous recombination deficiency, HRR homologous recombination repair, MRN Mre11-Rad50-Nbs1, NAD+ nicotinamide adenine dinucleotide, NHEJ non-homologous end joining, PARP poly (ADP-ribose) polymerase, PARylation poly (ADP-ribosyl)ation, SSB single-stranded breaks. Created with Biorender.com

Fig. 2

Mechanisms of PARPi resistance. (1) Restoration of homologous recombination repair. a Somatic reversion mutation restores the open reading frame and activity of HRR genes. b Epigenetic reversion by loss of methylation can restore BRCA1/RAD51 function. c Hypomorphic proteins, viz. BRCA1D11q isoform, retains partial activity due to an intact functional domain. d Restoration of end resection through loss of 53BP1 and Shieldin also promote PARPi resistance. (2) Alteration in PARP function due to a PARP1 mutations (R519C), or b Loss of PARG can inhibit PARylation and PARP trapping. (3) Stabilization of the RF. a HRD leads to collapse of the replication fork due to unchecked activity of nucleases such as MRE11, DNA2 and MUS81. Downregulation of these nucleases by loss of RF remodelers (MLL, EZH2, PTIP, SMARCAL1, HLTF) and FANCD2 overexpression promotes fork stabilization and promotes PARPi resistance. b RADX depletion restores fork stabilization by regulating RAD51. RF can also be stabilized by loss of regulation of G1/S cell cycle checkpoint secondary to E2F7 depletion. (4) Drug efflux and activation of alternate pathways can also cause PARPi resistance. 53BP1 TP53-binding protein, HRD homologous recombination deficiency, HRR homologous recombination repair, PARG poly (ADPribose) glycohydrolase, PARPi poly (ADP-ribose) polymerase inhibitor, PARylation poly (ADP-ribosyl)ation, RF replication fork. Created with Biorender.com

Fig. 3

PARPi resistance can be managed by either a PARPi rechallenge, especially in the context of platinum sensitivity; b Overcoming resistance: resistance mechanisms can be overcome through inhibiting angiogenesis, targeting cell cycle regulators, or combining with immune checkpoint inhibitors; or c Bypassing resistance: an alternative strategy is targeting the non-cross-resistant pathways that are independent of HRR. GR glucocorticoid receptors, HRR homologous recombination repair, ICI immune checkpoint inhibitor, PARPi poly (ADP-ribose) polymerase inhibitor. Created with Biorender.com