PARP Inhibitors in Ovarian Cancer: Resistance Mechanisms, Clinical Evidence, and Evolving Strategies

Abstract

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) into the management of ovarian cancer has transformed the treatment landscape for patients affected by this malignancy. However, as the use of PARPi expands into both frontline maintenance and recurrence settings, the emergence of drug resistance has become a significant clinical challenge in the treatment of these patients. Although platinum-based chemotherapy (PBC) and PARPi act through different mechanisms-PBC causes DNA damage while PARPi blocks its repair-both depend on the integrity of DNA damage repair (DDR) pathways, leading to overlapping mechanisms of resistance. Here, we review the key resistance mechanisms shared by PARPi and PBC, and then we discuss their clinical implications in the management of patients with ovarian cancer. We also examine clinical rationale supporting the hypothesis that prior PARPi exposure may reduce the efficacy of subsequent PBC in patients experiencing a disease recurrence. Furthermore, we review preliminary clinical data assessing the potential role of PARPi retreatment in patients who have previously progressed on PARPis.

Keywords: PARP inhibitors; drug resistance; ovarian neoplasms; platinum-based chemotherapy.

Figure 1

Mechanisms of resistance to PARP inhibitors and platinum-based therapies in cancer cells. This figure outlines the cellular mechanisms contributing to resistance against PARP inhibitors and platinum-based chemotherapy. It is divided into three key categories: DNA damage response (illustrated here by homologous recombination restoration), replication fork stabilization, and intracellular mechanisms such as an enhanced expression of drug efflux transporters and increased activation of oncogenic signaling pathways. ABCB1, ATP-binding cassette subfamily B member 1; BRCA1/2, breast cancer gene 1/2; DNA, deoxyribonucleic acid; DYNLL1, dynein light chain LC8-Type 1; HR, homologous recombination; HSP90, heat shock protein 90; MRE11, MRE11 homolog; PARPi, PARP inhibitor; PTIP, PAX interacting protein 1; RAD51, RAD51 recombinase; RAD51C/D, RAD51 homolog C/D; RADX, regulator of DNA replication fork stability; STAT3, signal transducer and activator of transcription 3; and 53BP1, tumor suppressor p53 binding protein 1.

Figure 2

Mechanism of action of PARP inhibitors and platinum-based chemotherapy. PARP inhibition blocks the repair of single-strand DNA breaks (SSBs), leading to replication fork stalling and collapse during the S-phase, which converts SSBs into double-strand breaks (DSBs). PBCs, on the other hand, introduce DNA adducts and intrastrand crosslinks, similarly stalling replication forks and producing DSBs. The resulting DSBs activate the MRN complex and ATM kinase, initiating the DNA damage response and triggering p53-mediated cell cycle arrest at both the G1/S and G2/M checkpoints if they remain unrepaired. These events eventually lead to genomic instability and cancer cell death. PARP, poly (ADP-ribose) polymerase; PBC, platinum-based chemotherapy; MRN, MRE11-RAD50-NBS1 complex; and ATM, ataxia telangiectasia mutated kinase.

Figure 3

Pathways of DNA damage response and the impact of PARP inhibition on cellular outcome. This figure illustrates various DNA damage types and their corresponding damage response pathways, highlighting the role of PARP in maintaining genomic stability and cell survival. Inhibition of PARP prevents these pathways, leading to the accumulation of damaged DNA and subsequent cell death. DNA, deoxyribonucleic acid; PARP, poly (ADP-Ribose) polymerase.