2. Academic Validation
  3. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor

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

  • Cancer Cell. 2014 Dec 8;26(6):909-922. doi: 10.1016/j.ccell.2014.10.019.
Camilla L Christensen 1,  Nicholas Kwiatkowski 2,  Brian J Abraham 2,  Julian Carretero 3,  Fatima Al-Shahrour 4,  Tinghu Zhang 5,  Edmond Chipumuro 6,  Grit S Herter-Sprie 1,  Esra A Akbay 1,  Abigail Altabef 1,  Jianming Zhang 5,  Takeshi Shimamura 7,  Marzia Capelletti 1,  Jakob B Reibel 1,  Jillian D Cavanaugh 1,  Peng Gao 1,  Yan Liu 1,  Signe R Michaelsen 8,  Hans S Poulsen 8,  Amir R Aref 1,  David A Barbie 1,  James E Bradner 1,  Rani E George 6,  Nathanael S Gray 5,  Richard A Young 9,  Kwok-Kin Wong 10
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
PMID: 25490451 DOI: 10.1016/j.ccell.2014.10.019
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.

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