The effects of somatic mutations on EGFR interaction with anti-EGFR monoclonal antibodies: Implication for acquired resistance.
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 EGFRS492R and EGFRV441I in complex with Cetuximab, EGFRR377S and EGFRS447Y in complex with Panitumumab, and EGFRV441I in complex with Necitumumab have a weakest binding affinity in comparison to EGFRWT 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.
['Tabasinezhad|Maryam|M|', 'Omidinia|Eskanadr|E|', 'Talebkhan|Yeganeh|Y|', 'Omrani|Mir Davood|MD|', 'Mahboudi|Fereidoun|F|', 'Ghaedi|Hamid|H|0000-0002-5034-0586', 'Wenzel|Wolfgang|W|']
D061067:Antibodies, Monoclonal, Humanized D000074322:Antineoplastic Agents, Immunological D000068818:Cetuximab D019008:Drug Resistance, Neoplasm D066246:ErbB Receptors D006801:Humans D020125:Mutation, Missense D009369:Neoplasms D000077544:Panitumumab D017354:Point Mutation D013816:Thermodynamics
mutation EGFR Cetuximab Panitumumab Necitumumab Matuzumab in silico