Related Experiment Video

Updated: Apr 17, 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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Published on: August 11, 2017

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Gefitinib-mediated reactive oxygen specie (ROS) instigates mitochondrial dysfunction and drug resistance in lung

Imoh S Okon1, Kathleen A Coughlan1, Miao Zhang1

  • 1From the Section of Molecular Medicine and.

The Journal of Biological Chemistry
|February 15, 2015
PubMed

Insights

Acquired resistance to gefitinib in lung cancer cells increases reactive oxygen species (ROS) and impairs mitochondria. Antioxidants may help overcome this resistance by mitigating ROS-induced damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Tyrosine kinase inhibitors (TKIs) like gefitinib are crucial for lung cancer treatment but efficacy is limited by acquired resistance.
  • Acquired resistance to TKIs leads to treatment failure and increased cancer mortality.
  • Understanding the mechanisms of acquired resistance is vital for developing more effective therapies.

Purpose of the Study:

  • To investigate the cellular mechanisms underlying acquired gefitinib resistance in lung adenocarcinoma (LAD) cells.
  • To elucidate the role of reactive oxygen species (ROS) and mitochondrial dysfunction in gefitinib resistance.
  • To explore potential therapeutic strategies targeting ROS-mediated resistance.

Main Methods:

  • Screening of LAD cell lines for EGFR expression and mutation status.
  • Generation of a gefitinib-resistant H1650 cell line through chronic drug selection.
  • Analysis of isogenic cells using microarray, Western blot, flow cytometry, confocal, and transmission electron microscopy.
  • Assessment of mitochondrial morphology and function, and ROS levels.

Main Results:

  • Chronic gefitinib treatment, while targeting EGFR, increased cellular ROS production.
  • Gefitinib-induced ROS correlated with epithelial-mesenchymal transition (EMT) and significant mitochondrial damage.
  • ROS scavengers partially restored mitochondrial function in resistant cells.
  • Cessation of gefitinib treatment led to normalized EMT gene expression in resistant cells.

Conclusions:

  • Chronic gefitinib treatment induces ROS and mitochondrial dysfunction, contributing to acquired resistance in lung cancer.
  • Targeting ROS with antioxidants may represent a viable strategy to overcome gefitinib resistance.
  • Further research into ROS-mediated pathways is warranted for improved lung cancer treatment.
Keywords:
Drug ResistanceEpithelial-Mesenchymal Transition (EMT)Gefitinib ResistanceMitochondriaMitochondrial DysfunctionProtein-tyrosine Kinase (Tyrosine-protein Kinase)Reactive Nitrogen Species (RNS)Reactive Oxygen Species (ROS)

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