Centre for Computational Science, Department of Chemistry, University College London, WC1H 0AJ, United Kingdom.
Mol Cancer Ther. 2012 Nov;11(11):2394-400. doi: 10.1158/1535-7163.MCT-12-0644-T. Epub 2012 Aug 3.
The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non-small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without.
表皮生长因子受体（EGFR）调节包括增殖、分化和凋亡在内的重要细胞过程。EGFR 在多种癌症中经常过表达，与疾病进展和治疗相关。临床研究表明，非小细胞肺癌患者的 EGFR 突变使肿瘤对酪氨酸激酶抑制剂敏感。在这项研究中，我们对配体自由状态下的野生型和 L858R 突变型 EGFR 进行了数微秒的分子动力学模拟。仔细检查结合口袋内的构象和相互作用表明，与野生型相反，突变型 EGFR 更喜欢结合吉非替尼（一种靶向抗癌药物）而不是 ATP，这解释了为什么吉非替尼在 EGFR 突变患者中比在没有突变的患者中更有效。
