From the Stony Brook University Cancer Center and Stony Brook University School of Medicine, Stony Brook, NY
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Timothy J. Kinsella, MD, Director, Stony Brook University Cancer Center, 3 Edmund Pellegrino Rd, Stony Brook, NY 11794-9444; e-mail: timothy.kinsella{at}stonybrook.edu
Overview: 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. 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, a great deal of progress has been made in elucidating these complex cellular and molecular networks involved in the DDR in human tumor and normal tissues using experimental in silico and in vivo models, to the extent that some 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, as well as ionizing radiation. Since many different types of human cancers can arise from genetic or epigenetic changes in the DDR and DNA repair pathways, recent developments in cancer therapeutics will be highlighted that attempt to target these specific tumor-related DDR/DNA repair defects as monotherapy or, more commonly, when combined with conventional cancer treatments.
