Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion
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Updated: Jan 19, 2026
In Vivo EPR Assessment of pH, pO2, Redox Status, and Concentrations of Phosphate and Glutathione in the Tumor Microenvironment
Published on: March 16, 2018
Mahsa Zarei1,2, Heng Du1, Amin H Nassar1
1Cancer Genetics Laboratory, Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Abstract:
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.
Insights
Tuberous sclerosis complex (TSC) tumors show dependence on transcription. Inhibiting CDK7 reduces tumor growth by lowering glutathione and increasing reactive oxygen species, offering a potential therapy for TSC-associated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder causing tumors in various organs.
- Loss of TSC1/TSC2 proteins activates mTORC1, promoting cell growth and anabolism.
- mTORC1 activation enhances mRNA transcription, suggesting a potential vulnerability in TSC-null cells.
Purpose of the Study:
- To investigate if TSC-null cells are dependent on transcriptional regulation.
- To evaluate the therapeutic potential of CDK7 inhibition in TSC-associated tumors.
Main Methods:
- Compared TSC1/TSC2-null cells with wild-type cells.
- Assessed sensitivity to pharmacological CDK7 inhibition.
- Conducted mechanistic studies on gene expression and cellular metabolism.
- Tested CDK7 inhibitor efficacy in mouse models (Tsc2-/- mice and TSC1-null bladder cancer xenografts).
Main Results:
- TSC1- or TSC2-null cells demonstrated sensitivity to CDK7 inhibition.
- CDK7 inhibition reduced glutathione levels and increased reactive oxygen species.
- This was linked to decreased expression of NRF2 and glutathione biosynthesis genes.
- CDK7 inhibitor treatment significantly reduced tumor volume in vivo and prevented regrowth in xenografts.
Conclusions:
- Aberrant mTORC1 activation in TSC confers a dependence on transcriptional regulation.
- CDK7 inhibition represents a promising therapeutic strategy for TSC-associated tumors.
- Targeting CDK7 may be effective for cancers with TSC1 or TSC2 mutations.
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