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Elevated ß-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.
Afiliação
  • Nakata A; 1] Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University [2] Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
  • Yoshida R; The Institute of Statistical Mathematics, 10-3 Midori-cho, Tachikawa Tokyo, 190-8562, Japan.
  • Yamaguchi R; Laboratory of Sequence Analysis, Institute of Medical Science, University of Tokyo.
  • Yamauchi M; Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
  • Tamada Y; Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
  • Fujita A; Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
  • Shimamura T; Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
  • Imoto S; Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
  • Higuchi T; The Institute of Statistical Mathematics, 10-3 Midori-cho, Tachikawa Tokyo, 190-8562, Japan.
  • Nomura M; Department of Surgery, Tokyo Medical University.
  • Kimura T; Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University.
  • Nokihara H; Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital.
  • Higashiyama M; Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases.
  • Kondoh K; Department of Thoracic, Endocrine Surgery and Oncology, Institute of Health Bioscience, The University of Tokushima Graduate School.
  • Nishihara H; Laboratory of Translational Pathology, Hokkaido University Graduate School of Medicine.
  • Tojo A; Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
  • Yano S; Division of Medical Oncology, Cancer Research Institute, Kanazawa University.
  • Miyano S; 1] Laboratory of Sequence Analysis, Institute of Medical Science, University of Tokyo [2] Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
  • Gotoh N; 1] Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University [2] Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
Sci Rep ; 5: 13076, 2015 Aug 13.
Article em En | MEDLINE | ID: mdl-26268703
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-ß-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 ß-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of ß-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of ß-catenin and treatment with a ß-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate ß-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-ß-catenin pathway to improve the efficacy of EGFR-TKIs.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinazolinas / Resistencia a Medicamentos Antineoplásicos / Beta Catenina / Receptores ErbB / Antineoplásicos Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinazolinas / Resistencia a Medicamentos Antineoplásicos / Beta Catenina / Receptores ErbB / Antineoplásicos Idioma: En Ano de publicação: 2015 Tipo de documento: Article