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Cancer Cell. 2014 Dec 8;26(6):909-922. doi: 10.1016/j.ccell.2014.10.019.

Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
2
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3
Departament de Fisiologia, Facultat de Farmacia, Universitat de Valencia, Valencia 46010, Spain.
4
Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
6
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA 02115, USA.
7
Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
8
Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
9
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.
10
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.

Erratum in

  • Cancer Cell. 2015 Jan 12;27(1):149.

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.

PMID:
25490451
PMCID:
PMC4261156
DOI:
10.1016/j.ccell.2014.10.019
[Indexed for MEDLINE]
Free PMC Article

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