PARP Inhibitors: The Cornerstone of DNA Repair-Targeted Therapies.

The activity and therapeutic licensing of poly(ADP-ribose) polymerase (PARP) inhibitors is the culmination of 50 years of research. However, the biology, mechanisms of action, adequate treatment combinations, and targeted populations for these agents need to be explored further. PARP activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway. This pathway is the default repair pathway in cells with deficient high-fidelity double-strand break homologous recombination (HR) repair, such as occurs with loss of BRCA1 or BRCA2 function. Therefore, inhibition of PARP function results in cell death in HR-deficient tumors, and sensitizes tumor cells to cytotoxic agents that induce DNA damage. Applications of PARP inhibition are now being expanded beyond tumors with HR deficiency to HR-competent tumors in which HR has been synthetically impaired through use of other agents given in combination with PARP inhibitors, or resulting from PARP inhibition in the setting of BRCA1 or BRCA2 loss.