CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer

Cell. 2014 Nov 20;159(5):1126-1139. doi: 10.1016/j.cell.2014.10.024. Epub 2014 Nov 6.

Abstract

The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / metabolism
  • Disease Models, Animal*
  • Humans
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / drug therapy*
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / metabolism*
  • Phenylenediamines / therapeutic use*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / therapeutic use*
  • Transcription, Genetic / drug effects

Substances

  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Phenylenediamines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • THZ1 compound
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase

Associated data

  • GEO/GSE62726