The DNA Damage Response: Roles in Cancer Etiology and Treatment

Abstract

Cancer is one of the highest causes of morbidity and mortality worldwide. Traditional chemotherapeutics are associated with toxic side effects due to a lack of specificity for cancer cells. A new and rapidly expanding class of drugs known as targeted therapeutics are being developed that have high therapeutic potential with less severe side effects in comparison to conventional chemotherapeutics. Targeted therapeutics are aimed at defects found in cancer cells that are not present in the highly-proliferative cells of normal tissues. These defects include dys regulated oncogenes and DNA repair defects that cause cells to rely heavily on the DNA damage response (DDR) and checkpoint signaling. This association indicates that the DDR may include promising targets for targeted therapeutics. Examples of such therapeutics currently under investigation and in clinical use are described here, including inhibitors of PARP, DNA-PKcs and the ATR-CHK1 signaling pathway. Targeted therapeutics not only offer the promise of killing cancers with reduced side effects, but are well suited to use in combination with other therapeutics to increase efficacy and kill cancers before drug-resistance can occur.