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

Nat Commun. 2017 Jan 30;8:14290. doi: 10.1038/ncomms14290.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Chromatin / metabolism
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism*
  • Female
  • Gain of Function Mutation
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lymphoma, T-Cell / drug therapy*
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenylenediamines / pharmacology
  • Phenylenediamines / therapeutic use
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription, Genetic / drug effects
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • BCL2 protein, human
  • Chromatin
  • Phenylenediamines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • Pyrroles
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • THZ1 compound
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase
  • obatoclax