β-catenin contributes to lung tumor development induced by EGFR mutations

Sohei Nakayama, Natasha Sng, Julian Carretero, Robert Welner, Yuichiro Hayashi, Mihoko Yamamoto, Alistair J. Tan, Norihiro Yamaguchi, Hiroyuki Yasuda, Danan Li, Kenzo Soejima, Ross A. Soo, Daniel B. Costa, Kwok Kin Wong, Susumu S. Kobayashi

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Abstract

The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that β-catenin is essential for development of EGFR-mutated lung cancers. β-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated β-catenin, leading to an increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that b-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.

Original languageEnglish
Pages (from-to)5891-5902
Number of pages12
JournalCancer Research
Volume74
Issue number20
DOIs
Publication statusPublished - 2014 Oct 15

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Nakayama, S., Sng, N., Carretero, J., Welner, R., Hayashi, Y., Yamamoto, M., Tan, A. J., Yamaguchi, N., Yasuda, H., Li, D., Soejima, K., Soo, R. A., Costa, D. B., Wong, K. K., & Kobayashi, S. S. (2014). β-catenin contributes to lung tumor development induced by EGFR mutations. Cancer Research, 74(20), 5891-5902. https://doi.org/10.1158/0008-5472.CAN-14-0184