Overview of DNA repair pathways, current targets, and clinical trials bench to clinic

Despite a longstanding understanding that many endogenous and exogenous agents can damage DNA, knowledge of how DNA repairs itself was largely an academic pursuit until the last two decades. The ongoing molecular characterization of the DNA damage response (DDR) and pathway crosstalk is invaluable in helping scientists learn how to modulate DNA repair activities therapeutically—ultimately translating discoveries into standalone or combination treatments, chemosensitizers or radiosensitizers. The study of DNA repair is also uncovering synthetic lethalities that are induced when an inhibitor capitalizes on a tumor-specific dysfunction or mutation. Although these targeted anticancer treatments are designed to cause less toxicity to normal cells, we still have much to learn before we can fully and optimally exploit this type of intervention. This chapter summarizes the history of DNA repair, explains important “firsts” in the field of DNA repair inhibition, overviews all DNA repair pathways, and suggests future directions for DNA repair inhibition.