Inhibition of DNA Repair as a Therapeutic Target

DNA is the target for many anticancer agents. In order to maintain genome stability and survive, we have evolved a complex DNA damage response (DDR) of damage signaling and repair. Dysregulation of the DDR is common in cancer, and loss of one component may be compensated by the function of another, on which the cancer cell may be uniquely dependent. Increased DDR pathways contribute to therapeutic resistance, but dysfunctional ones can result in vulnerability to DNA-damaging agents. This provides two rationales for inhibition of the DDR:

1. To reduce therapeutic resistance to DNA-damaging cancer therapy associated with enhanced DDR pathways

2. To selectively target tumor cells defective in one DDR pathway by targeting the complementary, backup pathway.

We describe here how anticancer agents damage DNA, the role of the DDR, and how inhibitors enhance the efficacy of radio- and chemotherapy and are effective as single agents, with examples of preclinical studies and clinical trials.