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Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer

Y Wang1, H Xia2, Z Zhuang3

  • 1Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China.

Cell Death & Disease
|May 17, 2014
PubMed

Insights

Axl kinase drives resistance to lung cancer drugs like gefitinib. Specific microRNAs (miRNAs) regulated by Axl, namely miR-374a and miR-548b, are key players in this resistance, offering potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Axl kinase is implicated in acquired resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).
  • The precise mechanisms underlying Axl's role in TKI resistance, particularly involving microRNAs (miRNAs), remain largely unelucidated.
  • MicroRNAs are critical regulators of gene expression and play significant roles in cancer development.

Purpose of the Study:

  • To investigate the role of miRNAs in Axl-mediated acquired gefitinib resistance in NSCLC.
  • To identify specific miRNAs modulated by Axl that contribute to gefitinib resistance.
  • To explore the therapeutic potential of targeting these Axl-modulated miRNAs.

Main Methods:

  • Analysis of Axl kinase-altered miRNAs in gefitinib-resistant NSCLC models.
  • Validation of the functional roles of identified miRNAs (miR-374a and miR-548b) in vitro and in vivo.
  • Assessment of the correlation between Axl, miRNA expression, and patient survival outcomes.

Main Results:

  • A panel of Axl kinase-altered miRNAs was identified in gefitinib-resistant NSCLC.
  • miR-374a and miR-548b, modulated by Axl, were found to be essential in regulating cell cycle arrest, apoptosis, epithelial-to-mesenchymal transition, migration, and tumorigenesis.
  • These miRNAs target Wnt5a and CCNB1 genes, respectively.
  • High Axl and miR-374a expression, and low miR-548b expression, correlate with poor postoperative disease-free survival in NSCLC patients.

Conclusions:

  • Axl-modulated miRNAs, specifically miR-374a and miR-548b, are critical mediators of gefitinib resistance in NSCLC.
  • Targeting these miRNAs may offer a novel therapeutic strategy to overcome or reverse gefitinib resistance in Axl-high NSCLC.
  • Expression levels of Axl, miR-374a, and miR-548b serve as potential prognostic biomarkers for NSCLC patients.

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