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Nat Commun. 2017 Jan 30;8:14290. doi: 10.1038/ncomms14290.

THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.

Author information

1
Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
2
Neuroimmunomodulation and Molecular Oncology Department, Institute for Biomedical Research (BIOMED), National Research Council of Argentina (CONICET), Catholic University of Argentina (UCA), C1107AFB Ciudad Autonoma de Buenos Aires, Argentina.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.

Abstract

Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.

PMID:
28134252
PMCID:
PMC5290269
DOI:
10.1038/ncomms14290
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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