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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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Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib

Jan Nyrop Jakobsen1, Eric Santoni-Rugiu2, Morten Grauslund2

  • 1Department of Oncology, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark.

Oncotarget
|June 15, 2018
PubMed
Abstract

Insights

EGFR-mutated non-small-cell lung cancer patients often have co-occurring mutations. These additional mutations in driver genes did not significantly affect response to erlotinib, suggesting potential for new therapeutic targets.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Non-small-cell lung cancer (NSCLC) with EGFR mutations typically responds to EGFR tyrosine kinase inhibitors (TKIs).
  • However, co-occurring mutations in other genes can potentially reduce TKI efficacy.
  • Understanding these co-mutations is crucial for optimizing NSCLC treatment.

Purpose of the Study:

  • To investigate the frequency and impact of co-mutations in EGFR-mutated NSCLC patients treated with erlotinib.
  • To identify specific co-mutations and their potential influence on treatment response.
  • To explore potential additional therapeutic targets in EGFR-mutated NSCLC.

Main Methods:

  • Analyzed 514 NSCLC patients for EGFR mutations using cobas® EGFR Mutation Test.
  • Performed FISH for MET amplification, IHC for MET/ALK expression, and NGS for co-mutations in EGFR-mutated, erlotinib-treated patients.
  • Assessed treatment response based on objective response rates and clinical outcomes.

Main Results:

  • Found EGFR mutations in 7% of patients; 2 had T790M resistance mutation, 1 had G719C/S768I double mutation.
  • Co-mutations were identified in 71% of NGS-analyzed tumors, with TP53 being the most frequent (67%).
  • Objective response to erlotinib was observed in 74% of patients, indicating that co-mutations did not significantly impair response.

Conclusions:

  • Co-mutations in cancer-driver genes are common in EGFR-mutated NSCLC.
  • Most identified co-mutations did not negatively impact response to first-line erlotinib.
  • These co-mutations may represent actionable targets for future NSCLC therapies.
Keywords:
EGFRNSCLCerlotinibmutationtarceva

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