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

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

5p.13076 , 2015-08-13 , Nature Publishing Group
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.

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