Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

Hanghang Zhang, Somnath Pandey, Meghan Travers, Hongxing Sun, George Morton, Jozef Madzo, Woonbok Chung, Jittasak Khowsathit, Oscar Perez-Leal, Carlos A. Barrero, Carmen Merali, Yasuyuki Okamoto, Takahiro Sato, Joshua Pan, Judit Garriga, Natarajan V. Bhanu, Johayra Simithy, Bela Patel, Jian Huang, Noël J.M. RaynalBenjamin A. Garcia, Marlene A. Jacobson, Cigall Kadoch, Salim Merali, Yi Zhang, Wayne Childers, Magid Abou-Gharbia, John Karanicolas, Stephen B. Baylin, Cynthia A. Zahnow, Jaroslav Jelinek, Xavier Graña, Jean Pierre J. Issa

Research output: Contribution to journalArticlepeer-review

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. Inhibition of a kinase typically associated with transcription elongation complexes leads to reactivation of tumor suppressor genes and increases sensitivity to immunotherapy in cancer models.

Original languageEnglish (US)
Pages (from-to)1244-1258.e26
JournalCell
Volume175
Issue number5
DOIs
StatePublished - Nov 15 2018

Keywords

  • BRG1
  • CDK9
  • DNA methylation
  • SMARCA4
  • SWI/SNF
  • drug development
  • epigenetic therapy
  • gene silencing
  • immunosensitization
  • kinase inhibitors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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