CDK7-dependent transcriptional addiction in triple-negative breast cancer

  • Cell. 2015 Sep 24;163(1):174-86. doi: 10.1016/j.cell.2015.08.063.
Yubao Wang  1 ,  Tinghu Zhang  1 ,  Nicholas Kwiatkowski  2 ,  Brian J Abraham  2 ,  Tong Ihn Lee  2 ,  Shaozhen Xie  1 ,  Haluk Yuzugullu  1 ,  Thanh Von  1 ,  Heyuan Li  3 ,  Ziao Lin  3 ,  Daniel G Stover  4 ,  Elgene Lim  4 ,  Zhigang C Wang  5 ,  J Dirk Iglehart  5 ,  Richard A Young  6 ,  Nathanael S Gray  7 ,  Jean J Zhao  8
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 6. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 8. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 26406377 DOI: 10.1016/j.cell.2015.08.063
Abstract

Triple-negative breast Cancer (TNBC) is a highly aggressive form of breast Cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing kinase inhibitors and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not hormone receptor-positive breast Cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An "Achilles cluster" of TNBC-specific genes is especially sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be a useful therapy for this challenging Cancer.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12280
    THZ2
    99.03%, CDK7 Inhibitor
    target: CDK
    Research Areas: Cancer