Cancer directly affects the lives of roughly 1 in 3 individuals and is the second leading cause of death from disease in the US and the developed world, with nearly 600,000 deaths per year in the US alone. Despite recent advancements, there is still an urgent need for new treatment options. Cancer involves a range of inherited or sporadic abnormalities (i.e., hallmarks), some of which include hyperproliferation and selective growth, metabolic reprogramming, and altered stress and DNA damage response (DDR) that favor survival (Reference). DNA damage, which is generated by intrinsic and extrinsic mechanisms, threatens the integrity of the genome, and if it persists can lead to disease and aging (Reference). In many situations, cancers arise from specific defects in DDR components, a characteristic that promotes mutagenesis and genomic instability that underlies and aids the process of carcinogenesis. 

 

In addition, DDR pathways are often upregulated as a mechanism to improve resistance against one of the  many genotoxic agents used in the treatment of neoplasia.  Given the prominent role of the DDR in cancer etiology and drug resistance, researchers have looked to exploit or attack DDR alterations using one of two strategies:  synthetic lethality (SL) or combinatorial therapy (Reference).  The former involves taking advantage of an inherited or sporadic defect in a cancer type to cause selective cell death, while the latter entails improving the efficacy of a genotoxin by targeting a relevant DDR factor, with both methods typically involving a small molecule inhibitor.  The SL approach has garnered particular clinical interest, due mainly to the recent advances made in cancer treatments for patients with breast cancer (BRCA) gene mutations, as they exhibit selective sensitivity to inhibitors of the DDR protein, poly(ADP)ribose polymerase (PARP).