PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting

Abstract

Poly(ADP-ribose) polymerases have shown true promise in early clinical studies due to reported activity in BRCA-associated cancers. PARP inhibitors may represent a potentially important new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. In addition, a more sophisticated understanding of the toxicity profile is required if PARP inhibitors are to be employed in the curative, rather than the palliative, setting. PARP inhibitors have successfully moved into clinical practice in the past few years, with approval granted from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past two years. The United States FDA approval of olaparib applies to fourth-line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval of olaparib for maintenance therapy in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. This review covers the current understanding of PARP, its inhibition, and the basis of the excitement surrounding these new agents. It also evaluates future approaches and directions required to achieve full understanding of the intricate interplay of these agents at the cellular level.

Keywords: BRCA; DNA; PARP; PARP1; PARP2; mutation; olaparib; ovarian cancer; poly(ADP-ribose) polymerases.

Fig. 1

A) Proper DNA repair mechanism with functional PARP protein and DNA repair proteins. B) Attempted DNA repair of SSB in the presence of PARP inhibitor resulting in DSB formation. BRCA-proficient cells have the ability to repair the DSB and restart; maintaining survival. BRCA-deficient cells are unable to repair the accumulating DSB–s which inevitably results in cell death