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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Transcription, Genetic*
  • Triple Negative Breast Neoplasms / genetics*

Substances

  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase

Associated data

  • GEO/GSE69107