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Krüppel-like factor 4 promotes c-Met amplification-mediated gefitinib resistance in non-small-cell lung cancer

Wei Feng1, Qianyi Xie1, Suo Liu1

  • 1Departments of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China.

Cancer Science
|April 7, 2018
PubMed

Insights

Krüppel-like factor 4 (KLF4) drives gefitinib resistance in non-small-cell lung cancer (NSCLC) with c-Met overexpression. Targeting KLF4 may overcome treatment resistance in these NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Gefitinib is a first-line treatment for advanced EGFR-mutated non-small-cell lung cancer (NSCLC).
  • Acquired resistance to gefitinib develops in many NSCLC patients within 9-14 months.
  • The mechanisms underlying gefitinib resistance, particularly in c-Met-overexpressing NSCLC, require further elucidation.

Purpose of the Study:

  • To investigate the role of Krüppel-like factor 4 (KLF4) in the development of gefitinib resistance in NSCLC.
  • To explore KLF4's interaction with c-Met signaling in gefitinib-resistant NSCLC cells.
  • To assess KLF4 as a potential therapeutic target for overcoming gefitinib resistance in NSCLC.

Main Methods:

  • Analysis of KLF4 expression in c-Met-overexpressing NSCLC cells and tissues.
  • In vitro studies involving KLF4 knockdown and overexpression in gefitinib-sensitive and resistant NSCLC cell lines.
  • Western blot analysis to examine protein expression and signaling pathway activation (c-Met/Akt/β-catenin).

Main Results:

  • KLF4 was overexpressed in c-Met-overexpressing NSCLC cells and tissues.
  • KLF4 knockdown reduced tumorigenicity and increased gefitinib sensitivity in c-Met-overexpressing resistant NSCLC cells.
  • KLF4 overexpression decreased gefitinib sensitivity in sensitive NSCLC cells.
  • KLF4 promoted gefitinib resistance by inhibiting apoptosis and activating the c-Met/Akt pathway.

Conclusions:

  • KLF4 plays a critical role in mediating gefitinib resistance in NSCLC with c-Met overexpression.
  • KLF4 influences gefitinib sensitivity by modulating apoptosis and the c-Met/Akt signaling pathway.
  • KLF4 represents a promising molecular target for the prevention and treatment of c-Met-overexpressing NSCLC.
Keywords:
AktKLF4NSCLCc-Metgefitinib resistance

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