The DNA Damaging Revolution: PARP Inhibitors and Beyond.

Cancer-specific DNA repair defects are abundant in malignant tissue and present an opportunity to capitalize on these aberrations for therapeutic benefit. Early preclinical data demonstrated the concept of synthetic lethality between BRCA genetic defects and pharmacologic PARP inhibition, suggesting that there may be monotherapy activity with this class of agents and supporting the early trial testing of this molecularly driven approach. Although the first foray into the clinic for PARP inhibitors was in combination with DNA-damaging cytotoxic agents, clinical development was limited by the more-than-additive toxicity, in particular dose-limiting myelosuppression. As more tolerable single agents, PARP inhibitors are now approved for the treatment of ovarian cancer in different settings and BRCA-mutant breast cancers. Beyond PARP inhibitors, there is now a large armamentarium of potent and relatively selective inhibitors in clinical trial testing against key targets involved in the DNA damage response (DDR), including ATR, ATM, CHK1/2, WEE1, and DNA-PK. These agents are being developed for patients with molecularly selected tumors and in rational combinations with other molecularly targeted agents and immune checkpoint inhibitors. We detail the clinical progress made in the development of PARP inhibitors, review rational combinations, and discuss the development of emerging inhibitors against novel DDR targets, including DNA repair proteins, DNA damage signaling, and DNA metabolism.