Department of Electrical Engineering, City University of Hong Kong, Kowloon, Hong Kong.
BMC Mol Cell Biol. 2021 Jun 10;22(1):34. doi: 10.1186/s12860-021-00358-6.
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.
表皮生长因子受体（EGFR）及其信号通路在肺癌的发病机制中起着至关重要的作用。通过干扰 EGFR 信号，EGFR 的突变可能导致癌症的进展或对 EGFR 靶向药物的耐药性的出现。
我们研究了 EGFR 突变与信号网络中 EGFR 受体酪氨酸激酶（RTK）相互作用之间的相关性，以揭示由 EGFR 突变引起的耐药机制。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。几何性质，即界面中原子实角度的匹配率和相互作用原子的质心距离，是基于 Alpha 形状建模提取的。对于几个 RTK 伴侣（c-Met、ErbB2 和 IGF-1R），结果表明，对于敏感 EGFR 突变体，EGFR-RTK 相互作用较为松散，而对于耐药突变体，相互作用更为紧密。这保证了由基因型决定的 EGFR-RTK 相互作用，并进一步通过 EGFR 突变引起的 EGFR-RTK 相互作用的放大提出了一种潜在的耐药机制。
这项研究将深入了解 EGFR 突变诱导的耐药机制，并促进创新药物的设计。
