title: THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.
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.
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.|Neuroimmunomodulation and Molecular Oncology Department, Institute for Biomedical Research (BIOMED), National Research Council of Argentina (CONICET), Catholic University of Argentina (UCA), C1107AFB Ciudad Autonoma de Buenos Aires, Argentina.
authors.forename: Florencia
authors.initials: F
authors.lastname: Cayrol
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Pannee
authors.initials: P
authors.lastname: Praditsuktavorn
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Tharu M
authors.initials: TM
authors.lastname: Fernando
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kwiatkowski
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Rosella
authors.initials: R
authors.lastname: Marullo
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: M Nieves
authors.initials: MN
authors.lastname: Calvo-Vidal
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Jude
authors.initials: J
authors.lastname: Phillip
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Kaipol
authors.initials: K
authors.lastname: Takpradit
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Roman
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: Gaudiano
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Ramona
authors.initials: R
authors.lastname: Crescenzo
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Neuroimmunomodulation and Molecular Oncology Department, Institute for Biomedical Research (BIOMED), National Research Council of Argentina (CONICET), Catholic University of Argentina (UCA), C1107AFB Ciudad Autonoma de Buenos Aires, Argentina.
authors.forename: Graciela
authors.initials: G
authors.lastname: Cremaschi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D000073659:Gain of Function Mutation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010655:Phenylenediamines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: C000595707:BCL2 protein, human; D002843:Chromatin; D007211:Indoles; D010655:Phenylenediamines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000596184:THZ1 compound; D018844:Cyclin-Dependent Kinases; C520962:obatoclax; D000095043:Cyclin-Dependent Kinase-Activating Kinase