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

FERNANDO TM; CALVO-VIDAL MN; YANG SN; GAUDIANO M; PRADITSUKTAVORN P; INGHIRAMI G; MARULLO R; GRAY NS; PERA B; ROMAN L; RUAN J; CREMASCHI G; CAYROL F; KWIATKOWSKI N; PHILLIP J; TAKPRADIT K; CRESCENZO R; ZHANG T; CERCHIETTI L

NATURE COMMUNICATIONS

SPRINGER NATURE

Año: 2017

2041-1723

Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response tochemotherapy and dismal survival. Identification of effective strategies to target PTCL biologyrepresents an urgent need. Here we report that PTCL are sensitive to transcription-targetingdrugs, 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 theactivating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1,CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression ofSTAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cellsto BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclaximproves 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 forthese patients.