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

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...

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Bibliographic Details
Published in:Scientific reports 2015-08, Vol.5, p.13076
Main Authors: 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
Format: Article
Language:English
Subjects:
Adenocarcinoma
AKT protein
Cytoplasm
Drug delivery
Epidermal growth factor
Epidermal growth factor receptors
Gefitinib
Gene expression
Kinases
Lung cancer
Mutation
Nuclei
Phosphorylation
Protein-tyrosine kinase receptors
β-Catenin
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Summary: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.
ISSN:2045-2322
DOI:10.1038/srep13076