Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion
| Autor: | Elizabeth P. Henske, John M. Asara, Heng Du, Hilaire C. Lam, Yubao Wang, Rachel E. Yan, Mahsa Zarei, Amin Nassar, David J. Kwiatkowski, Sneha Johnson, Tinghu Zhang, Krinio Giannikou |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities NF-E2-Related Factor 2 Immunology Cell Mice Nude mTORC1 Mechanistic Target of Rapamycin Complex 1 Phenylenediamines Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Tuberous Sclerosis Cell Line Tumor Neoplasms medicine Immunology and Allergy Animals Humans Research Articles Cells Cultured chemistry.chemical_classification Reactive oxygen species Chemistry Cell growth Gene Expression Profiling HEK 293 cells Glutathione Xenograft Model Antitumor Assays Cyclin-Dependent Kinases nervous system diseases Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure HEK293 Cells Pyrimidines 030220 oncology & carcinogenesis Mutation Cancer research Female TSC1 TSC2 Cyclin-Dependent Kinase-Activating Kinase |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Tuberous sclerosis complex (TSC) is a genetic disorder in which tumors develop due to TSC1/TSC2 loss and activation of mTORC1. Zarei et al. show that TSC tumors are sensitive to CDK7 inhibition, which reduces expression of NRF2 and glutathione synthetic genes, leading to glutathione depletion and ROS-mediated cell death. Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/− mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2. |
| Databáze: | OpenAIRE |
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