Zhou Huaxin, Fu Haohao, Liu Han, Shao Xueguang, Cai Wensheng
Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China.
Front Mol Biosci. 2022 May 30;9:922839. doi: 10.3389/fmolb.2022.922839. eCollection 2022.
The emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. However, the mechanism of the enhancement of the binding affinity of ATP to EGFR, which is of paramount importance for the development of new inhibitors, is still unclear. In this work, to explore the detailed mechanism of the drug resistance due to the T790M mutation, molecular dynamics simulations and absolute binding free energy calculations have been performed. The results show that the binding affinity of ATP with respect to the L858R/T790M mutant is higher compared with the L858R mutant, in good agreement with experiments. Further analysis demonstrates that the T790M mutation significantly changes the van der Waals interaction of ATP and the binding site. We also find that the favorable binding of ATP to the L858R/T790M mutant, compared with the L858R mutant, is due to a conformational change of the αC-helix, the A-loop and the P-loop of the latter induced by the T790M mutation. This change makes the interaction of ATP and P-loop, αC-helix in the L858R/T790M mutant higher than that in the L858R mutant, therefore increasing the binding affinity of ATP to EGFR. We believe the drug-resistance mechanism proposed in this study will provide valuable guidance for the design of drugs for NSCLC.
耐药性的出现可能会增加晚期非小细胞肺癌（NSCLC）患者的死亡率。厄洛替尼是用于治疗具有表皮生长因子受体（EGFR）L858R突变的NSCLC的有效一线抗肿瘤药物，其耐药性发生在EGFR的T790M突变之后，因为这种突变使得三磷酸腺苷（ATP）与EGFR的结合比厄洛替尼更有利。然而，对于开发新抑制剂至关重要的ATP与EGFR结合亲和力增强的机制仍不清楚。在这项工作中，为了探索由T790M突变引起的耐药性的详细机制，进行了分子动力学模拟和绝对结合自由能计算。结果表明，与L858R突变体相比，ATP对L858R/T790M突变体的结合亲和力更高，这与实验结果高度吻合。进一步分析表明，T790M突变显著改变了ATP与结合位点的范德华相互作用。我们还发现，与L858R突变体相比，ATP对L858R/T790M突变体的有利结合是由于T790M突变诱导的后者αC螺旋、A环和P环的构象变化。这种变化使得L858R/T790M突变体中ATP与P环、αC螺旋的相互作用高于L858R突变体，从而增加了ATP与EGFR的结合亲和力。我们相信本研究中提出的耐药机制将为NSCLC药物设计提供有价值的指导。
