2. Academic Validation
  3. CDK7-dependent transcriptional addiction in triple-negative breast cancer

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12280
    99.03%, CDK7 Inhibitor
    CDK