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Updated: Jul 21, 2025

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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EGFR-T790M Mutation-Derived Interactome Rerouted EGFR Translocation Contributing to Gefitinib Resistance in Non-Small

Pei-Shan Wu1, Miao-Hsia Lin2, Jye-Chian Hsiao3

  • 1Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.

Molecular & Cellular Proteomics : MCP
|July 26, 2023
PubMed

Insights

The T790M mutation causes resistance to lung cancer drugs. Inhibiting autophagy alongside TKIs may overcome this resistance by targeting EGFR degradation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Acquired resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) due to the T790M mutation is a significant clinical challenge.
  • Understanding how cancer cells adapt to drug perturbation is crucial for developing effective therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying TKI resistance by analyzing the epidermal growth factor receptor (EGFR) interactome in drug-sensitive and resistant NSCLC cells.
  • To identify potential therapeutic strategies to overcome acquired resistance.

Main Methods:

  • Affinity purification coupled with mass spectrometry was employed to investigate the EGFR interactome in TKI-sensitive and TKI-resistant NSCLC cell lines.
  • Cellular localization, protein interactions, and degradation pathways of EGFR were analyzed under gefitinib treatment.

Main Results:

  • The T790M mutation altered the EGFR interactome, leading to diverse subcellular distributions and enrichment in endocytic trafficking pathways.
  • Gefitinib treatment induced autophagy-mediated EGFR degradation in resistant cells; inhibiting autophagy enhanced gefitinib sensitivity.
  • In sensitive cells, gefitinib promoted EGFR translocation via Rab7 ubiquitination, potentially enhancing TKI efficacy.

Conclusions:

  • The T790M mutation reprograms the EGFR interactome, directing EGFR towards autophagy-mediated degradation as a resistance mechanism.
  • Combination therapy involving TKIs and autophagy inhibitors presents a promising strategy to overcome acquired TKI resistance in NSCLC.
Keywords:
T790M mutationTKI-resistanceautophagyepidermal growth factor receptornon-small cell lung cancerprotein-protein interactiontyrosine kinase inhibitor

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