Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep13076
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [25830111]
- MEXT
- Ministry of Health, Labor and Welfare of Japan
- Grants-in-Aid for Scientific Research [15H05912, 15K12139, 25830111, 15K20965, 25730173] Funding Source: KAKEN
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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-beta-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 beta-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of beta-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of beta-catenin and treatment with a beta-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate beta-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-beta-catenin pathway to improve the efficacy of EGFR-TKIs.
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