PARP Trapping Beyond Homologous Recombination and Platinum Sensitivity in Cancers

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPis) have recently been approved for the treatment of ovarian and breast cancers with BRCA mutations, as well as for maintenance therapies regardless of BRCA mutation for ovarian and primary peritoneal cancers that previously responded to platinum-based chemotherapy. The rationale of these indications is derived from the facts that cancer cells with BRCA mutations are defective in homologous recombination (HR), which confers synthetic lethality with PARPis, and that some of the sensitivity-determining factors for PARPis are shared with platinums. Although BRCA1 and BRCA2 are central for HR, more players within and beyond HR are emerging as response determinants to PARPis. Furthermore, there are similarities as well as differences in the DNA lesions and repair pathways induced by PARPis, platinums, and camptothecin topoisomerase 1 (TOP1) inhibitors. Here we review the sensitivity-determining factors for PARPis and the rationale for using PARPis as single agents and in combination therapy for cancers.