title: Targeting the S and G2 checkpoint to treat cancer.
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.
authors.affiliation: Newcastle University, Northern Institute for Cancer Research, Newcastle-upon-Tyne, UK.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Peter A
authors.initials: PA
authors.lastname: Stephens
authors.forename: Fiona K
authors.initials: FK
authors.lastname: Middleton
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical; D016195:G2 Phase / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016196:S Phase / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors