التفاصيل البيبلوغرافية
| العنوان: |
Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer |
| المؤلفون: |
Mrozek, Evelyn M., Bajaj, Vineeta, Guo, Yanan, Malinowska, Izabela A., Zhang, Jianming, Kwiatkowski, David J. |
| المساهمون: |
Calvisi, Diego, National Cancer Institute |
| المصدر: |
PLOS ONE ; volume 16, issue 4, page e0248380 ; ISSN 1932-6203 |
| بيانات النشر: |
Public Library of Science (PLoS) |
| سنة النشر: |
2021 |
| المجموعة: |
PLOS Publications (via CrossRef) |
| الوصف: |
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. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1371/journal.pone.0248380 |
| الإتاحة: |
https://doi.org/10.1371/journal.pone.0248380Test |
| حقوق: |
http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: |
edsbas.F57B0C51 |
| قاعدة البيانات: |
BASE |
