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

• DOI: 10.1038/ncomms14290
• Publication Date: 2017-01-30T10:26:02Z
• Authors: Florencia Cayrol; Pannee Praditsukt...; Tharu M. Fernando; Nicholas Kwiatkowski; Rosella Marullo; M. Nieves Calvo-V...; 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
• Keywords: PIM1

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