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Updated: May 5, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

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Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA

David A Nathanson1, Beatrice Gini, Jack Mottahedeh

  • 1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.

Science (New York, N.Y.)
|December 7, 2013
PubMed

Insights

Cancer cells adapt to EGFR tyrosine kinase inhibitors (TKIs) by altering epidermal growth factor receptor (EGFR) expression and extrachromosomal DNA. This dynamic resistance mechanism allows tumors to evade targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Intratumoral heterogeneity is a key factor in cancer drug resistance.
  • Mechanisms driving resistance to targeted therapies, particularly in glioblastoma, remain poorly understood.

Purpose of the Study:

  • To investigate the mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in glioblastoma.
  • To understand how tumor cells adapt and evade targeted therapies.

Main Methods:

  • Single-cell analyses were performed on patient-derived glioblastoma models and clinical samples.
  • EGFR expression levels and extrachromosomal DNA were analyzed in tumor cells treated with EGFR TKIs.

Main Results:

  • Tumor cells dynamically regulate mutant EGFR expression, leading to distinct cellular phenotypes and growth.
  • Resistance to EGFR TKIs emerges through the elimination of mutant EGFR from extrachromosomal DNA.
  • EGFR mutations reemerge on extrachromosomal DNA after drug withdrawal, indicating adaptive resistance.

Conclusions:

  • Cancer cells exhibit dynamic and adaptive resistance to EGFR TKIs by modulating EGFR expression and extrachromosomal DNA.
  • Targeting oncogenes maintained on extrachromosomal DNA presents a specific therapeutic challenge due to adaptive resistance mechanisms.

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