Journal
CANCER TREATMENT REVIEWS
Volume 40, Issue 1, Pages 109-117Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ctrv.2013.03.002
Keywords
ATR; Cancer; Replication stress; DNA damage; Radiation; Chemotherapy; Therapeutics
Categories
Funding
- Cancer Research UK
- Medical Research Council
- Oxford Cancer Imaging Centre
- NIHR Biomedical Research Centre, Oxford
- MRC [MC_PC_12004] Funding Source: UKRI
- Cancer Research UK [16466, 11563, 19276] Funding Source: researchfish
- Medical Research Council [MC_PC_12004] Funding Source: researchfish
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The ataxia telangiectasia and Rad3-related (ATR) plays an important role in maintaining genome integrity during DNA replication through the phosphorylation and activation of Chk1 and regulation of the DNA damage response. Preclinical studies have shown that disruption of ATR pathway can exacerbate the levels of replication stress in oncogene-driven murine tumors to promote cell killing. Additionally, inhibition of ATR can sensitise tumor cells to radiation or chemotherapy. Accumulating evidence suggests that targeting ATR can selectively sensitize cancer cells but not normal cells to DNA damage. Furthermore, in hypoxic conditions, ATR blockade results in overloading replication stress and DNA damage response causing cell death. Despite the attractiveness of ATR inhibition in the treatment of cancer, specific ATR inhibitors have remained elusive. In the last two years however, selective ATR inhibitors suitable for in vitro and - most recently - in vivo studies have been identified. In this article, we will review the literature on ATR function, its role in DDR and the potential of ATR inhibition to enhance the efficacy of radiation and chemotherapy. (C) 2013 Elsevier Ltd. All rights reserved.
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