The DNA Damage Response: Roles in Cancer Etiology and Treatment
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.
KeywordsTargeted therapeutics Synthetic lethality DNA damage response HR deficiency Chemotherapeutic resistance Oncogenic stress Checkpoint inhibition Replication stress ATR/ATM/DNA-PK/PARP/p53/BRCA
We would like to thank our support from the National Cancer Institute of the National Institutes of Health under award numbers: R41CA203436 (LB, OG, EJB) and 1R01CA189743 (EJB). Additional funding was provided through the Ben Franklin Technology Partners of Southeastern PA, an initiative of the Pennsylvania Department of Community and Economic Development funded by the Ben Franklin Technology Development Authority (LB, OG), the Pennsylvania Department of Health (EJB), The Basser Center for BRCA Research (EJB), and the Abramson Family Cancer Research Institute (EJB).
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