Newcastle University, Northern Institute for Cancer Research, Newcastle-upon-Tyne, UK.
Drug Discov Today. 2012 Mar;17(5-6):194-202. doi: 10.1016/j.drudis.2011.12.009. Epub 2011 Dec 15.
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.
细胞在 DNA 损伤后能否存活取决于激活检查点以停止增殖。大多数癌细胞的 G1 检查点失调，使它们依赖于 S 和 G2 检查点，而 S 和 G2 检查点由 ATR/Chk1 信号通路激活。因此，抑制 ATR 或 Chk1 应该可以选择性地使癌细胞对 DNA 损伤敏感。ATR 和 Chk1 的基因失活会破坏细胞周期阻滞，并增强暴露于 DNA 损伤剂后的细胞毒性。在临床前研究中使用小分子 Chk1 抑制剂也观察到了类似的效果，并且开始出现临床试验数据。最近，已经鉴定出有效的 ATR 抑制剂，这些抑制剂也可以在体外使癌细胞敏感。ATR 和 Chk1 抑制剂也可能导致在特定 DNA 修复途径有缺陷的肿瘤细胞中出现“合成致死”。
