DNA Repair Dysregulation in Cancer: From Molecular Mechanisms to Synthetic Lethal Opportunities

Targeted cancer therapies have excellent potential for increasing longterm patient survival while minimizing shortand long-term side effects of therapy including neurological problems and secondary cancers. DNA repair systems suppress genome instability that drives the acquisition of tumorigenic mutations. Most cancer therapeutics cause DNA damage, yet despite having DNA repair defects, tumors often display resistance to therapy because redundant repair pathways can process DNA damage effi ciently. By targeting the redundant repair pathways, tumors can be sensitized to endogenous and/or exogenous DNA damage, described as synthetic lethality or synthetic sensitivity. There have been notable successes in applying synthetic lethal and sensitive approaches to treat cancer, but challenges remain as tumors can acquire resistance due to their rapid evolution driven by ongoing genome instability. It is important to improve our understanding of DNA repair pathways to better exploit tumor weaknesses imparted by DNA repair defects.