Imam Ibrahim A, Al Adawi Shatha, Liu Xiaoqi, Ellingson Sally, Brainson Christine F, Moseley Hunter N B, Zinner Ralph, Zhang Shulin, Shao Qing
Department of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky, USA.
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
Proteins. 2025 Mar;93(3):673-683. doi: 10.1002/prot.26761. Epub 2024 Nov 4.
Acquired resistance to first-line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all-atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild-type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.
各种癌症对一线治疗产生的获得性耐药既会促进癌症复发，也会限制有效治疗。表皮生长因子受体（EGFR）突变情况就是如此，对于EGFR突变，继发性EGFR突变是赋予对共价抑制剂奥希替尼耐药性的主要机制之一。因此，更深入地了解与接受奥希替尼治疗的肿瘤中出现的EGFR突变相关的继发性突变耐药机制，对于加快开发创新治疗药物以克服获得性耐药非常重要。这项工作使用全原子分子动力学（MD）模拟来研究两种已报道的对奥希替尼耐药的EGFR突变体（L858R/L718Q和L858R/L792H）的构象变化。野生型EGFR激酶结构域和L858R突变体用作参考。我们的MD模拟结果表明，L718Q和L792H继发性突变均在活性口袋中的残基与水分子的残基之间诱导额外的氢键。这些额外的氢键减少了奥希替尼的共价结合靶点C797的暴露面积。额外的氢键还通过改变结构域中氨基酸残基的二级结构和灵活性来影响EGFR激酶结构域的结合亲和力。我们的工作突出了这两种已报道的突变如何改变残基-残基和残基-溶剂氢键，影响蛋白质结合特性，这可能有助于未来的药物发现。
