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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
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Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor

Tzu-Hua Chang1, Meng-Feng Tsai, Kang-Yi Su

  • 1Graduate Institute of Medical Sciences, National Defense Medical Center, #161 Sec. 6 Minquan E. Rd., Neihu Dist., Taipei City, Taiwan.

American Journal of Respiratory and Critical Care Medicine
|November 2, 2010
PubMed
Abstract

Insights

Slug, an epithelial-mesenchymal transition regulator, drives resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer. Targeting Slug may overcome TKI resistance in lung adenocarcinoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Non-small cell lung cancer (NSCLC) with EGFR mutations initially responds to EGFR tyrosine kinase inhibitors (TKIs).
  • Acquired resistance to EGFR TKIs is a major clinical challenge, leading to disease relapse.
  • Epithelial-mesenchymal transition (EMT) is implicated in TKI resistance, but its underlying molecular mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of EMT regulators in mediating resistance to gefitinib, an EGFR TKI.
  • To identify specific molecular targets for overcoming gefitinib resistance in NSCLC.

Main Methods:

  • Quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis were used to assess EMT regulator expression in gefitinib-sensitive and resistant NSCLC cells.
  • In vitro experiments involved gene silencing and overexpression of EMT regulators to evaluate their impact on gefitinib sensitivity.
  • In vivo efficacy was confirmed using a xenograft mouse model, and clinical samples from lung adenocarcinoma patients were analyzed.

Main Results:

  • Slug expression was significantly upregulated in gefitinib-resistant NSCLC cells compared to sensitive cells.
  • Slug knockdown resensitized resistant cells to gefitinib, while Slug overexpression conferred resistance in sensitive cells.
  • Slug silencing restored gefitinib-induced apoptosis via Bim upregulation and caspase-9 activation; Slug promoted tumor growth in vivo, even with gefitinib treatment.
  • Clinical samples showed higher Slug expression in TKI-resistant lung adenocarcinoma cells.

Conclusions:

  • Slug plays a critical role in the development of gefitinib resistance in NSCLC.
  • Slug represents a potential therapeutic target for overcoming resistance to EGFR TKIs in lung cancer patients.

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