Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival

Abstract

The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% displaying defective HRR. Poly ADP ribose polymerases (PARPs) are a family of enzymes that catalyse the transfer of ADP-ribose to target proteins, functioning in fundamental cellular processes including transcription, chromatin remodelling and DNA repair. In cells with deficient HRR, PARP inhibitors (PARPis) cause synthetic lethality leading to cell death. Despite the major advances that PARPis have heralded for women with ovarian cancer, questions and challenges remain, including: can the benefits of PARPis be brought to a wider range of women with ovarian cancer; can other drugs in clinical use function in a similar way or with greater efficacy than currently clinically approved PARPis; what can we learn from long-term responders to PARPis; can PARPis sensitise ovarian cancer cells to immunotherapy; and can synthetic lethal strategies be employed more broadly to develop new therapies for women with ovarian cancer. We examine these, and other, questions with focus on improving outcomes for women with ovarian cancer.

Keywords: BRCA; PARP; high-grade serous ovarian cancer; homologous recombination deficiency; homologous recombination repair; niraparib; olaparib; ovarian cancer; rucaparib; synthetic lethal.

Figure 1

Synthetic lethality occurs when a defect in the homologous recombination repair (HRR) pathway is combined with inhibition of poly (ADP-ribose) polymerase (PARP). (i) PARP binds to sites of single strand breaks (SSBs), PARylates substrates and recruits DNA repair proteins. (ii) PARP inhibitors (PARPis) bind PARP, preventing PARylation and blocking access of PARP to DNA lesions that results in double strand breaks (DSBs). (iii) PARPis can also work to trap PARP at the DNA, inhibiting the dissociation of PARP from DNA and leading to the generation of DSBs. In cells with defective HRR, DSBs are unable to be repaired, leading to cell death. Created with Biorender.com.

Figure 2

Discovery of PARP inhibitors and their introduction to the clinic. (A) Milestones in the discovery of PARP and clinical adoption of PARPis are recorded over time. Major milestones are indicated with a red diamond. All milestones are specific to the treatment of ovarian cancer, with the exception of talazoparib which was first approved for metastatic breast cancer and not currently approved for ovarian cancer. (B) Selected landmark clinical trials investigating progression-free survival (PFS) that were instrumental in clinical approval of PARPis, including in combination therapy, are shown. Increased PFS in treatment compared to placebo arms are represented. Additional months of PFS for treatment versus placebo groups are reported for the whole cohort (NCT00753545); BRCA mutant patients (NCT01847274 and NCT01968213); HRD positive patients including BRCA mutant (NCT02477644); HRD positive patients (NCT02655016). Detailed clinical trial information is reported in Supplementary Tables S1 and S2. For trials noted as active but not recruiting, the primary completion date for data collection is noted. FDA, Food and Drug Administration (US); NMPA, National Medical Products Administration (China). HRD, homologous recombination deficiency; HRR, Homologous Recombination Repair; PARPi, PARP inhibitor. Created with Biorender.com.

Figure 3

Chemical structures of clinically used PARP inhibitors. The chemical structures of PARP inhibitors (PARPis) are from ChEMBL database (www.ebi.ac.uk/chembl, accessed on 15 June 2022). * PARPis are listed by PARP trapping potency from highest to lowest [80]. ** There is no currently available data (N.A) for fuzuloparib PARP trapping potency. *** There is no currently available data for pamiparib trapping potency relative to other PARPis.

Figure 4

Mechanisms of PARP inhibitor resistance. There are four generally accepted mechanisms of PARPi resistance. (i) Homologous Recombination (HRR) restoration. The synthetic lethality is based on HRR deficiency and PARP inhibition. When HR reactivates in cancer cells for reasons including the occurrence of a reversion mutation, DNA damage can be repaired by the HRR pathway, cancer cells survive and become resistant to PARP inhibitors (PARPis). (ii) Stabilisation of the replication fork. Some HRR-associated proteins also function to stabilise stalled DNA replication forks. In HRR deficient cells (sensitive to PARPi), stalled replication forks will be degraded by DNA nucleases (e.g., MRE11, MUS81). PARPi resistant cells protect the replication fork by inhibiting the recruitment of DNA nucleases, therefore maintaining genomic stability. (iii) A PARP mutation can affect the ability of PARPi to bind PARP, leading to a decrease in PARP trapping. Mutated PARP can recruit other DNA repair proteins to correct single-strand breaks, leading to PARPi resistance and cell survival. (iv) Increase in drug efflux. Some PARPis (e.g., olaparib) are substrates of the transmembrane glycoprotein MDR1 (multi-drug resistance protein 1), also known as p-glycoprotein 1. By upregulating the activities of MDR1, PARPi is transported out of the cancer cells. Created with Biorender.com.