Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
Department of Genetics and Metabolism, Pasteur Institute of Iran, Tehran, Iran.
Proteins. 2020 Jan;88(1):3-14. doi: 10.1002/prot.25762. Epub 2019 Jul 2.
A number of mutations in the epidermal growth factor receptor (EGFR) have been identified that imparts resistance to anti-EGFR monoclonal antibodies (mAbs) in clinical and preclinical samples. Primary or acquired resistance to targeted therapy will eventually limit the clinical benefit of anticancer mAbs. The aim of the current study was to perform computational analysis to investigate the structural implications of the EGFR somatic mutations on its complexes with the four anti-EGFR mAbs (Cetuximab, Panitumumab, Necitumumab, and Matuzumab). Docking analysis and molecular dynamics (MD) simulations were performed to understand the plausible structural and dynamical implications caused by somatic mutations available in the Catalogue of Somatic Mutations in Cancer database on the EGFR and anti-EGFR mAbs. We found that EGFR and EGFR in complex with Cetuximab, EGFR and EGFR in complex with Panitumumab, and EGFR in complex with Necitumumab have a weakest binding affinity in comparison to EGFR in complex with the relevant mAb. Taken together with the results obtained from docking analysis and MD simulations, the present findings may suggest that, the S492R and V441I mutations confer resistance to Cetuximab, R377S and S447Y mutations mediate resistance to Panitumumab and finally, V441I mutation also confers resistance to Necitumumab.
已经鉴定出表皮生长因子受体 (EGFR) 的许多突变，这些突变赋予临床和临床前样本中抗 EGFR 单克隆抗体 (mAb) 的耐药性。针对靶向治疗的原发性或获得性耐药最终将限制抗癌 mAb 的临床获益。本研究的目的是进行计算分析，以研究 EGFR 体细胞突变对其与四种抗 EGFR mAb（西妥昔单抗、帕尼单抗、尼妥珠单抗和马妥珠单抗）复合物的结构影响。进行对接分析和分子动力学 (MD) 模拟，以了解 Catalogue of Somatic Mutations in Cancer 数据库中 EGFR 和抗 EGFR mAb 上存在的体细胞突变所导致的可能的结构和动力学影响。我们发现，与 EGFR 与相关 mAb 形成复合物的 EGFR 相比，EGFR 与西妥昔单抗形成复合物的 EGFR、EGFR 与帕尼单抗形成复合物的 EGFR 以及 EGFR 与尼妥珠单抗形成复合物的 EGFR 的结合亲和力较弱。结合对接分析和 MD 模拟的结果，本研究结果表明，S492R 和 V441I 突变赋予西妥昔单抗耐药性，R377S 和 S447Y 突变介导对帕尼单抗的耐药性，而 V441I 突变也赋予对尼妥珠单抗的耐药性。
