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

Florencia Cayrol, Pannee Praditsuktavorn, Tharu M. Fernando, Nicholas Kwiatkowski, Rosella Marullo, M. Nieves Calvo-Vidal, Jude Phillip, Benet Pera, Shao Ning Yang, Kaipol Takpradit, Lidia Roman, Marcello Gaudiano, Ramona Crescenzo, Jia Ruan, Giorgio Inghirami, Tinghu Zhang, Graciela Cremaschi, Nathanael S. Gray and Leandro Cerchietti ()
Additional contact information
Florencia Cayrol: Weill Cornell Medicine
Pannee Praditsuktavorn: Weill Cornell Medicine
Tharu M. Fernando: Weill Cornell Medicine
Nicholas Kwiatkowski: Dana-Farber Cancer Institute, Harvard Medical School
Rosella Marullo: Weill Cornell Medicine
M. Nieves Calvo-Vidal: Weill Cornell Medicine
Jude Phillip: Weill Cornell Medicine
Benet Pera: Weill Cornell Medicine
Shao Ning Yang: Weill Cornell Medicine
Kaipol Takpradit: Weill Cornell Medicine
Lidia Roman: Weill Cornell Medicine
Marcello Gaudiano: Weill Cornell Medicine
Ramona Crescenzo: Weill Cornell Medicine
Jia Ruan: Weill Cornell Medicine
Giorgio Inghirami: Weill Cornell Medicine
Tinghu Zhang: Dana-Farber Cancer Institute, Harvard Medical School
Graciela Cremaschi: Institute for Biomedical Research (BIOMED), National Research Council of Argentina (CONICET), Catholic University of Argentina (UCA)
Nathanael S. Gray: Dana-Farber Cancer Institute, Harvard Medical School
Leandro Cerchietti: Weill Cornell Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14290

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