[Clinical development of PARP inhibitors]

DNA repair pathways enable tumor cells to survive chemotherapy- and radiation-induced DNA damage. Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. PARP inhibitors are an area of active clinical investigation in oncology, as they exploit synthetic lethality in tumors with defective homologous recombination(HR)and potentiate the cytotoxic effect of chemotherapy and radiation. Defects in HR pathways are not restricted to BRCA-associated tumors, however, various other cancer types may also be characterized by a lack of HR and are hence susceptible to PARP inhibition. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation both in vitro and in vivo. To date, at least nine different companies have initiated clinical oncology trials with PARP inhibitors, ranging in stages from phase 0 to 3. Recent studies have indicated that tumor cells with defective HR repair pathways, the classic example being BRCA mutations, are exquisitely sensitive to PARP inhibitors. This review summarizes findings and concepts regarding the role of PARP inhibition, as well as the challenges that will be faced in the clinical development of these agents. The identification of predictive markers for sensitivity to PARP inhibition represents a priority area for research.