Understanding DNA Damage Response and DNA Repair Pathways: Applications to More Targeted Cancer Therapeutics

Radiation therapy and many of the commonly used cancer chemotherapeutic drugs target DNA for cytotoxicity. Indeed, the subsequent DNA damage response (DDR) to these cancer treatments in both malignant and normal cells/tissues determines the therapeutic index (TI) of the treatment. The DDR is a complex set of cell processes involving multiple DNA repair, cell cycle regulation, and cell death/survival pathways (or networks) with both damage specificity and coordination of the DDR to different types of DNA damage. Over the last decade, significant progress has been made in elucidating these complex cellular and molecular networks involved in the DDR in human tumor and normal tissues. Based on what has been learned about these processes using experimental in vitro and in vivo models, DDR and DNA pathways are now potential targets for cancer therapy. This article presents an overview of our current understanding of the DDR, including the key DNA repair pathways involved in determining the cytotoxicity to several classes of chemotherapy drugs (CT) as well as ionizing radiation (IR). Since many different types of human cancers can arise from genetic or epigenetic changes in the DDR and DNA repair pathways, this article also covers recent developments in cancer therapeutics that attempt to target these specific tumor-related DDR/DNA repair defects as monotherapy or, more commonly, when combined with conventional cancer treatments.