Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer
| Autor: | Yanan Guo, Izabela A. Malinowska, Evelyn M Mrozek, David J. Kwiatkowski, Vineeta Bajaj, Jianming Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Kinase Inhibitors Ganetespib Cancer Treatment mTORC1 Biochemistry Tuberous Sclerosis Complex 1 Protein Hsp90 inhibitor chemistry.chemical_compound Mice 0302 clinical medicine Cell Signaling Tuberous Sclerosis Neoplasms Null cell Medicine and Health Sciences Enzyme Inhibitors Benzoxazoles Multidisciplinary Chemistry Pharmaceutics Liver Diseases TOR Serine-Threonine Kinases Nonsense Mutation Cell cycle Oncology Nephrology 030220 oncology & carcinogenesis Renal Cancer Medicine Growth inhibition Research Article Signal Transduction congenital hereditary and neonatal diseases and abnormalities Science Mice Nude Gastroenterology and Hepatology Mechanistic Target of Rapamycin Complex 1 03 medical and health sciences Drug Therapy Cell Line Tumor Gastrointestinal Tumors Tuberous Sclerosis Complex 2 Protein Genetics Animals Humans HSP90 Heat-Shock Proteins Naphthyridines Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Cell growth Carcinoma Cancers and Neoplasms Biology and Life Sciences Hepatocellular Carcinoma Cell Biology Xenograft Model Antitumor Assays Mice Inbred C57BL 030104 developmental biology Pyrimidines Mutation Cancer research Enzymology Drug Screening Assays Antitumor |
| Zdroj: | PLoS ONE PLoS ONE, Vol 16, Iss 4, p e0248380 (2021) |
| ISSN: | 1932-6203 |
| Popis: | Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay. |
| Databáze: | OpenAIRE |
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