Mechanism of Action of PARP Inhibitors

Abstract

The selective vulnerability of BRCA1/2-mutated (BRCA mut) cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors provides one of the best examples of synthetic lethality that has been translated into the clinic. The success of this approach has led to a paradigm shift, with four PARP inhibitors now approved by the US Food and Drug Administration (FDA) for the treatment of ovarian, breast, prostate, and/or pancreatic cancers with BRCA mut. Furthermore, recent preclinical and clinical data suggest that many other types of solid tumors might also benefit from PARP inhibitors, regardless of their BRCA mut status. Despite this progress, resistance to PARP inhibitors is frequently observed in the clinic, which is, at least in part, due to the incomplete understanding of the mechanism of action of PARP inhibitors. In this review, we summarize the diverse processes underlying the signaling mechanisms of the PARP enzymes. We also discuss recent progress in utilizing these mechanistic insights for overcoming PARP inhibitor resistance, developing predictive biomarker assays, designing rational combination therapies, and, finally, developing the next-generation PARP1-targeting agents with a more complete and durable therapeutic response.