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

Sci Rep. 2015 Aug 13:5:13076. doi: 10.1038/srep13076.

Abstract

There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • Gefitinib
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Mutation, Missense
  • Protein Transport
  • Quinazolines / pharmacology*
  • Transcription, Genetic
  • Transcriptional Activation
  • Up-Regulation
  • Wnt Signaling Pathway
  • beta Catenin / physiology*

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • Quinazolines
  • beta Catenin
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib