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Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugsElevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
"/Nakata, Asuka(1000070597921)/"Nakata, Asuka 
,
"/Yoshida, Ryo/"Yoshida, Ryo ,
"/Yamaguchi, Rui/"Yamaguchi, Rui ,
"/Yamauchi, Mai/"Yamauchi, Mai ,
"/Tamada, Yoshinori/"Tamada, Yoshinori ,
"/Fujita, Andre/"Fujita, Andre ,
"/Shimamura, Teppei/"Shimamura, Teppei ,
"/Imoto, Seiya/"Imoto, Seiya ,
"/Higuchi, Tomoyuki/"Higuchi, Tomoyuki ,
"/Nomura, Masaharu(1000040424494)/"Nomura, Masaharu ,
"/Kimura, Tatsuo/"Kimura, Tatsuo ,
"/Nokihara, Hiroshi/"Nokihara, Hiroshi ,
"/Higashiyama, Masahiko/"Higashiyama, Masahiko ,
"/Kondoh, Kazuya/"Kondoh, Kazuya ,
"/Nishihara, Hiroshi/"Nishihara, Hiroshi ,
"/Tojo, Arinobu/"Tojo, Arinobu ,
"/Yano, Seiji(1000030294672)/"Yano, Seiji ,
"/Miyano, Satoru/"Miyano, Satoru ,
"/Gotoh, Noriko(1000010251448)/"Gotoh, Noriko
5p.13076 , 2015-08-13 , Nature Publishing Group
ISSN:2045-2322
Description
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.
Full-Text
http://dspace.lib.kanazawa-u.ac.jp/dspace/bitstream/2297/45447/1/CA-PR-GOTO-N-13076.pdf
