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The effects of somatic mutations on EGFR interaction with anti‐EGFR monoclonal antibodies: Implication for acquired resistance
Author(s) -
Tabasinezhad Maryam,
Omidinia Eskanadr,
Talebkhan Yeganeh,
Omrani Mir Davood,
Mahboudi Fereidoun,
Ghaedi Hamid,
Wenzel Wolfgang
Publication year - 2020
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25762
Subject(s) - panitumumab , cetuximab , epidermal growth factor receptor , monoclonal antibody , somatic cell , egfr inhibitors , cancer research , monoclonal , mutation , docking (animal) , biology , medicine , receptor , genetics , antibody , gene , nursing
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 S492R and EGFR V441I in complex with Cetuximab, EGFR R377S and EGFR S447Y in complex with Panitumumab, and EGFR V441I in complex with Necitumumab have a weakest binding affinity in comparison to EGFR WT 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.