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

Asuka Nakata, Ryo Yoshida, Rui Yamaguchi, Mai Yamauchi, Yoshinori Tamada, Andre Fujita, Teppei Shimamura, Seiya Imoto, Tomoyuki Higuchi, Masaharu Nomura, Tatsuo Kimura, Hiroshi Nokihara, Masahiko Higashiyama, Kazuya Kondoh, Hiroshi Nishihara, Arinobu Tojo, Seiji Yano, Satoru Miyano, Noriko Gotoh

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23 Citations (Scopus)

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.

Original languageEnglish
Article number13076
JournalScientific reports
Volume5
DOIs
Publication statusPublished - 2015 Aug 13

ASJC Scopus subject areas

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    Nakata, A., Yoshida, R., Yamaguchi, R., Yamauchi, M., Tamada, Y., Fujita, A., Shimamura, T., Imoto, S., Higuchi, T., Nomura, M., Kimura, T., Nokihara, H., Higashiyama, M., Kondoh, K., Nishihara, H., Tojo, A., Yano, S., Miyano, S., & Gotoh, N. (2015). Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs. Scientific reports, 5, [13076]. https://doi.org/10.1038/srep13076