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, Leandro Cerchietti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number14290
JournalNature communications
Volume8
DOIs
StatePublished - Jan 30 2017
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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