PARP inhibitors in the management of breast cancer: current data and future prospects

Abstract

Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics.

Fig. 1

Current model for PARP role in DNA damage repair and PARP inhibition – BRCA mutation synthetic lethality. a When single-strand break (SSB) is detected, PARP recruitment and activation leads to SSB repair through poly(ADP-ribosyl)ation (PARylation) of histones and chromatin remodeling enzymes, auto-PARylation of PARP, and recruitment of PARP-dependent DNA repair proteins. Repaired DNA can undergo replication determining cell survival. b In the presence of PARP inhibitors, PARPs recruited to DNA-damage sites are no longer able to activate PARP-dependent repair systems and to dissociate from DNA (due to catalytic activity inhibition and/or direct trapping), determining replication fork (RF) stalling during DNA replication. Stalled RF eventually collapse creating double strand break (DSB). DSB can be repaired by homologous recombination (HR) and replication may restart, leading to cell survival. In BRCA-deficient cells, HR is impaired, thus DSB cannot be efficiently repaired; in this context, DSB accumulate determining cell death