TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma
| Autor: | Barbara S. Slusher, Jill P. Mesirov, Scott L. Pomeroy, Charles G. Eberhart, Brad Poore, Khoa Pham, Tenley C. Archer, Madison James, Rachael E. Maynard, Jesse Alt, Eric H. Raabe, Youngran Park, Allison Hanaford, Pablo Tamayo |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Antineoplastic Agents Mechanistic Target of Rapamycin Complex 2 mTORC1 Mechanistic Target of Rapamycin Complex 1 Article Carboplatin Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Humans Medicine Cerebellar Neoplasms Protein Kinase Inhibitors neoplasms Sapanisertib PI3K/AKT/mTOR pathway Cell Proliferation Medulloblastoma Chemotherapy business.industry Cell growth medicine.disease Glutathione Xenograft Model Antitumor Assays nervous system diseases stomatognathic diseases 030104 developmental biology Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Cancer research Female business |
| Zdroj: | Cancer Lett |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2021.02.001 |
| Popis: | Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma. |
| Databáze: | OpenAIRE |
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