Related Experiment Video

Updated: Jun 26, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

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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The Impact of Inadequate Exposure to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors on the Development

Daniela Frezzetti1, Vincenza Caridi1, Laura Marra1

  • 1Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy.

International Journal of Molecular Sciences
|May 11, 2024
PubMed

Insights

Suboptimal doses of EGFR-tyrosine kinase inhibitors (TKIs) can drive resistance in non-small-cell lung cancer (NSCLC) by promoting partial epithelial-mesenchymal transition (EMT) and enhancing cancer stem cell markers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Non-small-cell lung cancer (NSCLC) patients with EGFR mutations often develop resistance to EGFR-tyrosine kinase inhibitors (TKIs).
  • Mechanisms of acquired resistance to suboptimal EGFR-TKI doses, resulting from inadequate drug exposure, are not well understood.

Purpose of the Study:

  • To investigate the molecular mechanisms of acquired resistance to suboptimal gefitinib doses in EGFR-mutant NSCLC.
  • To compare resistance mechanisms induced by low-dose gefitinib exposure versus higher doses.

Main Methods:

  • Established gefitinib-resistant HCC827 and PC9 cell lines using suboptimal fixed and intermittent doses.
  • Analyzed EGFR signaling activation, epithelial-mesenchymal transition (EMT) markers, and cell motility.
  • Performed whole transcriptome RNA sequencing to identify molecular differences.

Main Results:

  • Low-dose gefitinib exposure induced partial EMT, increased cell migration, and enhanced cancer stem cell marker transcription, particularly in HCC827 cells.
  • Gefitinib-resistant HCC827 cells exhibited increased secretion of transforming growth factor (TGF)-β1.
  • Inhibition of TGF-β1 partially restored gefitinib sensitivity in resistant cells.

Conclusions:

  • Different levels of EGFR-TKI exposure can promote distinct acquired resistance mechanisms in NSCLC.
  • Suboptimal EGFR-TKI dosing may drive resistance through EMT induction and cancer stem cell pathway activation.
  • Targeting TGF-β1 may be a potential strategy to overcome gefitinib resistance in NSCLC.
Keywords:
EGFR mutationsEGFR–tyrosine kinase inhibitorsnon-small-cell lung cancerresistance

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