Targeting the S and G2 checkpoint to treat cancer

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  2. Dr Tao Chen
  3. Dr Peter Stephens
  4. Fiona Middleton
  5. Professor Nicola Curtin
Author(s)Chen T, Stephens PA, Middleton FK, Curtin NJ
Publication type Article
JournalDrug Discovery Today
Year2012
Volume17
Issue5-6
Pages194-202
ISSN (print)1359-6446
ISSN (electronic)1878-5832
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Cell survival following DNA damage depends on activating checkpoints to arrest proliferation. Most cancer cells have dysregulated G1 checkpoints making them dependent on their S and G2 checkpoints, which are activated by ATR/Chk1 signalling. Thus, inhibiting ATR or Chk1 should selectively sensitise cancer cells to DNA damage. Genetic inactivation of ATR and Chk1 abrogates cell cycle arrest and enhances cytotoxicity following exposure to DNA-damaging agents. Similar effects were seen with small-molecule Chk1 inhibitors in preclinical studies, and clinical trial data are starting to emerge. Recently, potent ATR inhibitors have been identified that also sensitise cancer cells in vitro. ATR and Chk1 inhibitors might also cause 'synthetic lethality' in tumour cells defective in defined DNA repair pathways
PublisherElsevier Ltd
URLhttp://dx.doi.org/10.1016/j.drudis.2011.12.009
DOI10.1016/j.drudis.2011.12.009
PubMed id22192883
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