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J Exp Med. 2019 Sep 10. pii: jem.20190251. doi: 10.1084/jem.20190251. [Epub ahead of print]

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion.

Author information

1
Cancer Genetics Laboratory, Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
2
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX.
3
Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
6
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
7
Cancer Genetics Laboratory, Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA dk@rics.bwh.harvard.edu.
#
Contributed equally

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.

PMID:
31506280
DOI:
10.1084/jem.20190251

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