Prevalence and molecular correlates of acquired EGFR resistance mutations in non-small cell lung cancer (NSCLC)

Related Experiment Video

Updated: May 13, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

10.5K

Luis E Raez1, Yasmine Baca2, Jennifer R Ribeiro2

  • 1Thoracic Oncology Program, Memorial Cancer Institute/Florida Atlantic University, Miami, FL, USA.

Expert Review of Anticancer Therapy
|April 16, 2025
PubMed
Abstract

Insights

Acquired resistance mutations in EGFR-mutant non-small cell lung cancer (NSCLC) are infrequent. Next-generation sequencing (NGS) is recommended for NSCLC that becomes resistant to EGFR tyrosine kinase inhibitors (TKIs).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for non-small cell lung cancer (NSCLC) with EGFR mutations.
  • Acquired resistance to EGFR TKIs is a significant clinical challenge in NSCLC management.
  • Understanding the prevalence and molecular landscape of resistance mechanisms is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To determine the frequency of EGFR resistance mutations in a large, real-world cohort of EGFR-mutated NSCLC patients.
  • To identify molecular co-alterations associated with EGFR resistance mutations.
  • To evaluate the clinical significance of specific resistance mutations, including those emerging after osimertinib treatment.

Main Methods:

  • Analysis of 46,505 NSCLC tumors profiled by next-generation sequencing (NGS) and immunohistochemistry.
  • Extraction of patient treatment and outcome data from insurance claims.
  • Identification and characterization of EGFR sensitizing and resistance mutations, along with co-occurring genetic alterations.

Main Results:

  • EGFR sensitizing mutations were found in 3,885 NSCLC patients; 71 patients harbored EGFR resistance mutations.
  • Common co-alterations with resistance mutations included TP53 (50%), PD-L1 positivity (40%), gLOH (20%), and CTNNB1 (23.2%).
  • L718 mutations were observed, particularly with L858R mutations and post-osimertinib treatment in a subset of patients.

Conclusions:

  • Acquired EGFR resistance mutations in NSCLC exhibit a low observed frequency in molecularly profiled tumors, potentially due to limited re-testing.
  • While T790M and C797S are known resistance mutations, L718 mutations represent another significant finding, especially in osimertinib-treated patients.
  • These findings underscore the importance of NGS evaluation for NSCLC that develops resistance to EGFR TKIs.
Keywords:
EGFREGFR resistance mutationsL718 mutationLung cancerosimertinibreceptor tyrosine kinase inhibitor

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