PARP Inhibitors in Breast and Ovarian Cancer

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.

Keywords: BRACA2; BRCA1; PARP inhibitor; breast cancer; ovarian cancer.

Figure 1

Figure describing the synthetic lethality interaction between PARPs and BRCA1/2. PARP binds to the single-strand DNA break sites, and results in the PARylation of target proteins and recruitment of the DNA damage repair effectors. In HR-deficient tumour cells (BRCA1-, BRCA2- or PALB2-deficient cells) treated with PARPi, NHEJ is the only pathway initiated in double-strand DNA repair, which leads to accumulation of genome instability and cell death for the low fidelity.

Figure 2

Causes and mechanisms of PARP inhibitor resistance: (1) restoration of homologous recombination; (2) stabilization of replication fork; (3) upregulation of drug efflux pumps; (4) downregulation of NHEJ; and (5) PARP1 and PARG mutations.