Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

Cell. 2018 Nov 15;175(5):1244-1258.e26. doi: 10.1016/j.cell.2018.09.051. Epub 2018 Oct 25.

Abstract

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

Keywords: BRG1; CDK9; DNA methylation; SMARCA4; SWI/SNF; drug development; epigenetic therapy; gene silencing; immunosensitization; kinase inhibitors.

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 Line, Tumor
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Methylation
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Small Molecule Libraries
  • Transcription Factors
  • Cyclin-Dependent Kinase 9
  • SMARCA4 protein, human
  • DNA Helicases