mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids
| العنوان: | mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids |
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| المؤلفون: | Teresa Gagliano, Ettore C. degli Uberti, Maria Rosaria Ambrosio, Mariaenrica Bellio, Federico Rea, Daniela Molè, Erica Gentilin, Marco Schiavon, Maria Chiara Zatelli, Federico Tagliati, Narciso Giorgio Cavallesco, Luigi Gaetano Andriolo |
| المصدر: | Endocrine-Related Cancer. 20:463-475 |
| بيانات النشر: | Bioscientifica, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Male, Cancer Research, Lung Neoplasms, Endocrinology, Diabetes and Metabolism, Drug Resistance, Pharmacology, Bronchial carcinoids, Phosphatidylinositol 3-Kinases, Endocrinology, bronchial carcinoids, mTOR inhibitors, mTOR resistance, predictive markers, mTOR inhibitors, mTOR resistance, Predictive markers, Phosphoinositide-3 Kinase Inhibitors, Mitogen-Activated Protein Kinase 1, Tumor, Mitogen-Activated Protein Kinase 3, TOR Serine-Threonine Kinases, Imidazoles, Ribosomal Protein S6 Kinases, 70-kDa, Middle Aged, Diabetes and Metabolism, Oncology, Quinolines, Female, medicine.drug, Adult, Cell Survival, Antineoplastic Agents, Carcinoid Tumor, Biology, NO, Cell Line, Young Adult, Cyclin D1, Downregulation and upregulation, Cell Line, Tumor, medicine, Humans, Everolimus, Viability assay, Protein kinase B, PI3K/AKT/mTOR pathway, Aged, Sirolimus, Ribosomal Protein S6 Kinases, RPTOR, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-akt, 70-kDa, Apoptosis, Neoplasm |
| الوصف: | Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the ‘resistant’ BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. ‘Resistant’ cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs. |
| تدمد: | 1479-6821 1351-0088 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d568ceee734719990b032710ffa4a70Test https://doi.org/10.1530/erc-13-0042Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4d568ceee734719990b032710ffa4a70 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14796821 13510088 |
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