title: Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.
abstract: Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Christensen
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kwiatkowski
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: Departament de Fisiologia, Facultat de Farmacia, Universitat de Valencia, Valencia 46010, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA 02115, USA.
authors.forename: Edmond
authors.initials: E
authors.lastname: Chipumuro
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Altabef
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jakob B
authors.initials: JB
authors.lastname: Reibel
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jillian D
authors.initials: JD
authors.lastname: Cavanaugh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
authors.forename: Signe R
authors.initials: SR
authors.lastname: Michaelsen
authors.affiliation: Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
authors.forename: Hans S
authors.initials: HS
authors.lastname: Poulsen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Amir R
authors.initials: AR
authors.lastname: Aref
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA 02115, USA.
authors.forename: Rani E
authors.initials: RE
authors.lastname: George
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: kwong1@partners.org.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental; D017422:Sequence Analysis, DNA; D055752:Small Cell Lung Carcinoma; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases