Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells
| Autor: | Christine Pirker, Walter Berger, Thomas Gruenberger, Anita Brandstetter, Martin Filipits, Harald Puhalla, Beata Herberger, Sabine Novak, Katharina Schmid |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
medicine.medical_specialty Cell Survival Blotting Western Cetuximab Biology Antibodies Monoclonal Humanized Erlotinib Hydrochloride Phosphatidylinositol 3-Kinases Internal medicine Cell Line Tumor medicine Humans Growth factor receptor inhibitor Epidermal growth factor receptor Protein Kinase Inhibitors PI3K/AKT/mTOR pathway EGFR inhibitors Cell Proliferation Sirolimus Antibiotics Antineoplastic Dose-Response Relationship Drug Cell growth TOR Serine-Threonine Kinases Antibodies Monoclonal Drug Synergism Immunohistochemistry ErbB Receptors Endocrinology Biliary Tract Neoplasms Oncology Mutation Cancer research biology.protein Quinazolines Erlotinib Mitogen-Activated Protein Kinases Protein Kinases medicine.drug Signal Transduction |
| Zdroj: | Molecular cancer therapeutics. 8(6) |
| ISSN: | 1538-8514 |
| Popis: | The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials. [Mol Cancer Ther 2009;8(6):1547–56] |
| Databáze: | OpenAIRE |
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