L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites.
L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites.
复制标题
L1198F 突变通过改变抑制剂和 ATP 结合位点的构象使克唑替尼对 ALK 重新敏感
DOI：
10.3390/ijms18030482
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发表时间：
2017-02-24
影响因子：
5.6
通讯作者：
Zhao Q
中科院分区：
文献类型：
--
作者：
Li J;Sun R;Wu Y;Song M;Li J;Yang Q;Chen X;Bao J;Zhao Q
间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌（NSCLC）小分子抑制剂治疗的疗效受到获得性耐药的极大挑战。最近的一项研究报告了最新一代抑制剂耐药突变L1198F导致对克唑替尼的再敏感，克唑替尼是美国食品药品监督管理局（FDA）批准的第一种用于治疗ALK阳性NSCLC的药物。为了克服这些抑制剂的获得性耐药性，了解这种极其罕见的事件是如何发生的非常重要。在这项研究中，我们利用分子动力学（MD）模拟剖析的分子机制。我们的MD结果显示，ALK的L1198F突变导致抑制剂位点的构象变化，并改变了ALK与克唑替尼和劳拉替尼的结合亲和力。L1198F突变也影响ALK的自激活，这一点得到了His1124和Tyr1278作为参与ATP结合和磷酸化的关键氨基酸的鉴定的支持。我们的研究结果对于设计更特异和有效的抑制剂用于治疗ALK阳性NSCLC和其他类型的癌症具有价值。
The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors. In this study, we exploited molecular dynamics (MD) simulation to dissect the molecular mechanisms. Our MD results revealed that L1198F mutation of ALK resulted in the conformational change at the inhibitor site and altered the binding affinity of ALK to crizotinib and lorlatinib. L1198F mutation also affected the autoactivation of ALK as supported by the identification of His1124 and Tyr1278 as critical amino acids involved in ATP binding and phosphorylation. Our findings are valuable for designing more specific and potent inhibitors for the treatment of ALK-positive NSCLC and other types of cancer.