TY - JOUR
T1 - THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
AU - Cayrol, Florencia
AU - Praditsuktavorn, Pannee
AU - Fernando, Tharu M.
AU - Kwiatkowski, Nicholas
AU - Marullo, Rosella
AU - Calvo-Vidal, M. Nieves
AU - Phillip, Jude
AU - Pera, Benet
AU - Yang, Shao Ning
AU - Takpradit, Kaipol
AU - Roman, Lidia
AU - Gaudiano, Marcello
AU - Crescenzo, Ramona
AU - Ruan, Jia
AU - Inghirami, Giorgio
AU - Zhang, Tinghu
AU - Cremaschi, Graciela
AU - Gray, Nathanael S.
AU - Cerchietti, Leandro
PY - 2017/1/30
Y1 - 2017/1/30
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms14290
DO - 10.1038/ncomms14290
M3 - Article
C2 - 28134252
AN - SCOPUS:85010933916
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 14290
ER -