Inhibition of β-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation

Yosuke Togashi, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Introduction: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). β-Catenin is a key component of the Wnt/β-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells. Methods and Results: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of β-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a β-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the β-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the β-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that β-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation. Conclusion: Our findings indicate that β-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.

Original languageEnglish
Pages (from-to)93-101
Number of pages9
JournalJournal of Thoracic Oncology
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

Keywords

  • Epidermal growth factor receptor T790M mutation
  • Epidermal growth factor receptor tyrosine kinase inhibitor
  • Non-small-cell lung cancer
  • Stem cell-like properties
  • β-Catenin

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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