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Targeting the S and G2 checkpoint to treat cancer

Lookup NU author(s): Dr Tao Chen, Dr Peter Stephens, Fiona Middleton, Professor Nicola Curtin

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Abstract

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


Publication metadata

Author(s): Chen T, Stephens PA, Middleton FK, Curtin NJ

Publication type: Article

Journal: Drug Discovery Today

Year: 2012

Volume: 17

Issue: 5-6

Pages: 194-202

Print publication date: 14/12/2011

ISSN (print): 1359-6446

ISSN (electronic): 1878-5832

Publisher: Elsevier Ltd

URL: http://dx.doi.org/10.1016/j.drudis.2011.12.009

DOI: 10.1016/j.drudis.2011.12.009

PubMed id: 22192883


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