The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma
| Autor: | Javad Nazarian, Charles G. Eberhart, Manabu Natsumeda, Sridevi Yadavilli, Madhuri Kambhampati, Katherine E. Warren, Eric H. Raabe, Jeffrey Rubens, Harpreet Kaur, Louis Rodgers, Laura Asnaghi, Hiroaki Miyahara, Isabella Taylor |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology Radiation-Sensitizing Agents Time Factors Apoptosis mTORC1 Mice SCID Radiation Tolerance 0302 clinical medicine Cell Movement Mice Inbred NOD Brain Stem Neoplasms Phosphorylation Sapanisertib Benzoxazoles Kinase TOR Serine-Threonine Kinases Chemoradiotherapy Glioma Oncology 030220 oncology & carcinogenesis biological phenomena cell phenomena and immunity Signal Transduction medicine.medical_specialty Mechanistic Target of Rapamycin Complex 2 Biology Mechanistic Target of Rapamycin Complex 1 Article 03 medical and health sciences Cell Line Tumor medicine PTEN Animals Humans Neoplasm Invasiveness Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Dose-Response Relationship Drug Cell growth Ribosomal Protein S6 Kinases Xenograft Model Antitumor Assays 030104 developmental biology Pyrimidines Multiprotein Complexes Cancer research biology.protein Proto-Oncogene Proteins c-akt |
| Popis: | Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKTS473 and p-S6S240/244 and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment. |
| Databáze: | OpenAIRE |
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