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
  • 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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