mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
| العنوان: | mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer |
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| المؤلفون: | Li Geng, Ping Zhang, Guangyi Wang, Feng Wei, Yandong Zhang, Yan Liu |
| المصدر: | International Journal of Molecular Sciences, Vol 16, Iss 2, Pp 3267-3282 (2015) International Journal of Molecular Sciences Volume 16 Issue 2 Pages 3267-3282 |
| بيانات النشر: | MDPI AG, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | pancreatic cancer, mTORC1, mTORC2, lcsh:Chemistry, Epidermal growth factor receptor, lcsh:QH301-705.5, Spectroscopy, EGFR inhibitors, biology, TOR Serine-Threonine Kinases, Forkhead Transcription Factors, General Medicine, feedback activation, Tumor Burden, Up-Regulation, Computer Science Applications, ErbB Receptors, Female, Erlotinib, EGFR signaling, Signal Transduction, medicine.drug, cell resistance, medicine.medical_specialty, Morpholines, Antineoplastic Agents, Article, Catalysis, Inorganic Chemistry, Erlotinib Hydrochloride, Cell Line, Tumor, Internal medicine, medicine, Animals, Humans, mTORC1/2 kinase, Physical and Theoretical Chemistry, Protein Kinase Inhibitors, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, Organic Chemistry, RPTOR, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, Disease Models, Animal, Endocrinology, lcsh:Biology (General), lcsh:QD1-999, Quinazolines, Cancer research, biology.protein, FoxO1/3a, Proto-Oncogene Proteins c-akt |
| الوصف: | The mammalian target of rapamycin (mTOR) is dysregulated in diverse cancers and contributes to tumor progression and drug resistance. The first generation of mTOR inhibitors have failed to show clinical efficiency in treating pancreatic cancers due in part to the feedback relief of the insulin-like growth factor-1 receptor (IGF-1R)-AKT signaling pathway. The second generation of mTOR inhibitors, such as AZD8055, could inhibit AKT activation upon mTOR complex 2 (mTORC2) inhibition. However, whether this generation of mTOR inhibitors can obtain satisfactory activities in pancreatic cancer therapy remains unclear. In this study, we found AZD8055 did not show great improvement compared with everolimus, AZD8055 induced a temporal inhibition of AKT kinase activities and AKT was then rephosphorylated. Additionally, we found that AZD8055-induced transient AKT inhibition increased the expression and activation of epidermal growth factor receptor (EGFR) by releasing its transcriptional factors Fork-head box O 1/3a (FoxO1/3a), which might contribute to cell resistance to AZD8055. The in vitro and in vivo experiments further indicated the combination of AZD8055 and erlotinib synergistically inhibited the mTORC1/C2 signaling pathway, EGFR/AKT feedback activation, and cell growth, as well as suppressed the progression of pancreatic cancer in a xenograft model. This study provides a rationale and strategy for overcoming AZD8055 resistance by a combined treatment with the EGFR inhibitor erlotinib in pancreatic cancer therapy. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1422-0067 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6c3ca43f465de1dcfb1e983836a550baTest http://www.mdpi.com/1422-0067/16/2/3267Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6c3ca43f465de1dcfb1e983836a550ba |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14220067 |
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