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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

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The effects of somatic mutations on EGFR interaction with anti-EGFR monoclonal antibodies: Implication for acquired

Maryam Tabasinezhad1, Eskanadr Omidinia2, Yeganeh Talebkhan1

  • 1Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.

Proteins
|June 23, 2019
PubMed

Insights

Specific epidermal growth factor receptor (EGFR) mutations cause resistance to anti-EGFR monoclonal antibodies (mAbs). Computational analysis revealed how these mutations affect drug binding, identifying key mutations conferring resistance to Cetuximab, Panitumumab, and Necitumumab.

Area of Science:

  • Oncology
  • Structural Biology
  • Computational Chemistry

Background:

  • Mutations in the epidermal growth factor receptor (EGFR) are a known cause of resistance to targeted cancer therapies, specifically anti-EGFR monoclonal antibodies (mAbs).
  • Understanding the structural basis of this resistance is crucial for developing more effective cancer treatments.

Purpose of the Study:

  • To computationally investigate the structural impact of EGFR somatic mutations on their binding affinity with four anti-EGFR mAbs: Cetuximab, Panitumumab, Necitumumab, and Matuzumab.
  • To identify specific EGFR mutations that confer resistance to these therapeutic antibodies.

Main Methods:

  • Docking analysis and molecular dynamics (MD) simulations were employed to assess the binding interactions between mutated EGFR and anti-EGFR mAbs.
  • Somatic mutations were sourced from the Catalogue of Somatic Mutations in Cancer database.

Main Results:

  • EGFR mutations S492R and V441I showed weakest binding affinity with Cetuximab.
  • EGFR mutations R377S and S447Y exhibited weakest binding affinity with Panitumumab.
  • EGFR mutation V441I displayed weakest binding affinity with Necitumumab when compared to wild-type EGFR.

Conclusions:

  • The EGFR mutations S492R and V441I are implicated in Cetuximab resistance.
  • Mutations R377S and S447Y may mediate resistance to Panitumumab.
  • The V441I mutation is suggested to confer resistance to Necitumumab, underscoring the role of specific EGFR mutations in antibody-based therapy resistance.
Keywords:
CetuximabEGFRMatuzumabNecitumumabPanitumumabin silicomutation

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