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Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs

Asuka Nakata1, Ryo Yoshida2, Rui Yamaguchi3

  • 11] Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University [2] Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.

Scientific Reports
|August 14, 2015
PubMed

Insights

The Akt-β-catenin pathway is a common resistance mechanism in lung cancer treated with EGFR inhibitors. Targeting this pathway may restore sensitivity to these vital lung cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Lung cancer has a high mortality rate, with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) showing efficacy in EGFR-mutated lung adenocarcinoma.
  • Primary and acquired resistance to EGFR-TKIs is a significant clinical challenge, limiting treatment effectiveness.
  • While Akt kinase activation is implicated in resistance, its specific targets remain unclear.

Purpose of the Study:

  • To investigate the role of the Akt-β-catenin pathway as a potential common resistance mechanism to EGFR-TKIs in lung cancer.
  • To identify molecular alterations associated with gefitinib resistance in lung adenocarcinoma cells.
  • To explore therapeutic strategies combining EGFR-TKIs with interventions targeting the Akt-β-catenin pathway.

Main Methods:

  • Analysis of gene expression profiles in gefitinib-resistant PC9M2 cells compared to sensitive PC9 cells.
  • Assessment of Akt and GSK3 phosphorylation, and β-catenin localization in resistant cells.
  • Evaluation of the effect of β-catenin knockdown and inhibition on gefitinib sensitivity.
  • Examination of β-catenin accumulation in lung adenocarcinoma tissues from resistant patients.

Main Results:

  • Gefitinib-resistant PC9M2 cells exhibited increased expression of Axin, a β-catenin target gene.
  • Elevated phosphorylation of Akt and GSK3, and accumulation of β-catenin in the cytoplasm/nucleus were observed in resistant cells.
  • Knockdown or inhibition of β-catenin partially restored gefitinib sensitivity in resistant cells.
  • Lung adenocarcinoma tissues from resistant patients showed a trend towards cytoplasmic β-catenin accumulation.

Conclusions:

  • The Akt-β-catenin pathway represents a common resistance mechanism to EGFR-TKIs in lung adenocarcinoma.
  • Targeting the Akt-β-catenin pathway offers a potential strategy to overcome or prevent resistance to EGFR-TKIs.
  • Combination therapy involving EGFR-TKIs and Akt-β-catenin pathway inhibitors may improve treatment efficacy in lung cancer patients.

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