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

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-?-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 ?-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of ?-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of ?-catenin and treatment with a ?-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate ?-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-?-catenin pathway to improve the efficacy of EGFR-TKIs.

SUBMITTER: Nakata A

PROVIDER: S-EPMC4535059 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Nakata Asuka A Yoshida Ryo R Yamaguchi Rui R Yamauchi Mai M Tamada Yoshinori Y Fujita Andre A Shimamura Teppei T Imoto Seiya S Higuchi Tomoyuki T Nomura Masaharu M Kimura Tatsuo T Nokihara Hiroshi H Higashiyama Masahiko M Kondoh Kazuya K Nishihara Hiroshi H Tojo Arinobu A Yano Seiji S Miyano Satoru S Gotoh Noriko N

Scientific reports 20150813

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 ana ...[more]

PMID: 26268703

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Project description:Background & aimsWnt/beta-catenin activation is observed in normal liver development, regeneration, and liver cancer. Our aim was to elucidate the regulation and mechanism of this pathway in liver.MethodsWe report the generation and characterization of liver-specific nonmutated beta-catenin-overexpressing transgenic mice. Transgenic livers were examined for their morphology and phenotype by histology, proliferation, apoptosis, and microarray analysis.ResultsTransgenic livers displayed a significant increase in cytoplasmic, membranous, and nuclear beta-catenin in hepatocytes as compared with their wild-type littermates, which display a predominant membranous localization only. A 15%-20% increase in the liver weight-body weight ratio was evident in transgenic mice secondary to increased hepatocyte proliferation. Microarray analysis showed differential expression of approximately 400 genes in the transgenic livers. Epidermal growth factor receptor RNA and protein and increased levels of activated epidermal growth factor receptor and Stat3 were observed in the transgenic livers. Epidermal growth factor receptor promoter analysis showed a T-cell factor-binding site, and subsequent reporter assay confirmed epidermal growth factor receptor activation in response to Wnt-3A treatment that was abrogated by frizzled related protein 1, a known Wnt antagonist. Epidermal growth factor receptor inhibition successfully decreased liver size in transgenic mice. Next, 7 of 10 hepatoblastomas displayed simultaneous beta-catenin and epidermal growth factor receptor up-regulation, thus suggesting a strong relationship between these 2 proteins in tumors.Conclusionsbeta-Catenin transgenic mice show an in vivo hepatotrophic effect secondary to increased basal hepatocyte proliferation. Epidermal growth factor receptor seems to be a direct target of the pathway, and epidermal growth factor receptor activation might contribute toward some mitogenic effects of increased beta-catenin in liver: epidermal growth factor receptor inhibition might be useful in such states.

Dataset Information

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

Publications

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

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