Epidermal growth factor receptor (EGFR) and its signaling pathways play a vital role in pathogenesis of lung cancer. By disturbing EGFR signaling, mutations of EGFR may lead to progression of cancer or the emergence of resistance to EGFR-targeted drugs. We investigated the correlation between EGFR mutations and EGFR-receptor tyrosine kinase (RTK) crosstalk in the signaling network, in order to uncover the drug resistance mechanism induced by EGFR mutations. For several EGFR wild type (WT) or mutated proteins, we measured the EGFR-RTK interactions using several computational methods based on molecular dynamics (MD) simulations, including geometrical characterization of the interfaces and conventional estimation of free energy of binding. Geometrical properties, namely the matching rate of atomic solid angles in the interfaces and center-of-mass distances between interacting atoms, were extracted relying on Alpha Shape modeling. For a couple of RTK partners (c-Met, ErbB2 and IGF-1R), results have shown a looser EGFR-RTK crosstalk for the drug-sensitive EGFR mutant while a tighter crosstalk for the drug-resistant mutant. It guarantees the genotype-determined EGFR-RTK crosstalk, and further proposes a potential drug resistance mechanism by amplified EGFR-RTK crosstalk induced by EGFR mutations. This study will lead to a deeper understanding of EGFR mutation-induced drug resistance mechanisms and promote the design of innovative drugs.

中文翻译：

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分子动力学模拟揭示基因型决定的 EGFR-RTK 异二聚化及其对肺癌治疗耐药性的影响

表皮生长因子受体（EGFR）及其信号通路在肺癌的发病机制中发挥着至关重要的作用。通过干扰 EGFR 信号传导，EGFR 突变可能导致癌症进展或出现对 EGFR 靶向药物的耐药性。我们研究了EGFR突变与信号网络中EGFR受体酪氨酸激酶（RTK）串扰之间的相关性，以揭示EGFR突变诱导的耐药机制。对于几种 EGFR 野生型 (WT) 或突变蛋白，我们使用几种基于分子动力学 (MD) 模拟的计算方法测量了 EGFR-RTK 相互作用，包括界面的几何特征和结合自由能的常规估计。几何特性，即界面中原子立体角的匹配率和相互作用原子之间的质心距离，是依靠阿尔法形状模型提取的。对于几个 RTK 伙伴（c-Met、ErbB2 和 IGF-1R），结果显示药物敏感 EGFR 突变体的 EGFR-RTK 串扰较宽松，而耐药突变体的串扰较严格。它保证了基因型决定的 EGFR-RTK 串扰，并通过 EGFR 突变诱导的放大 EGFR-RTK 串扰进一步提出了潜在的耐药机制。这项研究将有助于更深入地了解EGFR突变诱导的耐药机制，并促进创新药物的设计。