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

Published on: May 20, 2020

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EGFR L792H and G796R: Two Novel Mutations Mediating Resistance to the Third-Generation EGFR Tyrosine Kinase Inhibitor

Qi Zhang1, Xu-Chao Zhang2, Jin-Ji Yang2

  • 1Southern Medical University, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
|June 2, 2018
PubMed
Abstract

Insights

New EGFR mutations, L792H and G796R, cause resistance to osimertinib in non-small cell lung cancer. These findings highlight the need for novel treatment strategies to overcome acquired resistance to targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is approved for advanced non-small cell lung cancer (NSCLC) with the EGFR T790M mutation.
  • Acquired resistance to osimertinib is a significant clinical challenge, necessitating research into its underlying mechanisms.

Observation:

  • Next-generation sequencing identified novel EGFR mutations, L792H and G796R, in patients with lung adenocarcinoma treated with osimertinib.
  • These mutations were found in cis with the T790M resistance mutation, conferring reduced sensitivity to osimertinib.

Findings:

  • In vitro studies demonstrated that EGFR L792H and G796R mutations significantly decrease sensitivity to osimertinib.
  • Structural modeling revealed that these mutations disrupt osimertinib binding by altering ligand interaction or hinge loop conformation.
  • Combinations like cetuximab with EAI045 were ineffective against these emergent resistance mutations.

Implications:

  • The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations confer resistance to osimertinib, impacting treatment efficacy.
  • Development of precise treatment strategies and novel combinational approaches is crucial for patients with these low-frequency resistance mutations.
Keywords:
Acquired drug-resistanceEGFR TKIsG796RL792HOsimertinib

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