@article{c57c92563e634e47ae3a66b986ddc059,
title = "Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer",
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.",
keywords = "BRG1, CDK9, DNA methylation, SMARCA4, SWI/SNF, drug development, epigenetic therapy, gene silencing, immunosensitization, kinase inhibitors",
author = "Hanghang Zhang and Somnath Pandey and Meghan Travers and Hongxing Sun and George Morton and Jozef Madzo and Woonbok Chung and Jittasak Khowsathit and Oscar Perez-Leal and Barrero, {Carlos A.} and Carmen Merali and Yasuyuki Okamoto and Takahiro Sato and Joshua Pan and Judit Garriga and Bhanu, {Natarajan V.} and Johayra Simithy and Bela Patel and Jian Huang and Raynal, {No{\"e}l J.M.} and Garcia, {Benjamin A.} and Jacobson, {Marlene A.} and Cigall Kadoch and Salim Merali and Yi Zhang and Wayne Childers and Magid Abou-Gharbia and John Karanicolas and Baylin, {Stephen B.} and Zahnow, {Cynthia A.} and Jaroslav Jelinek and Xavier Gra{\~n}a and Issa, {Jean Pierre J.}",
note = "Funding Information: We thank Dr. Roland Dunbrack for providing a superposed set of all CDK kinase structures from the Protein Data Bank. We are grateful to OpenEye Scientific Software (Santa Fe, NM) for providing an academic license for the use of ROCS and OMEGA. We thank Dr. Bassel E. Sawaya for providing CDK9 constructs for the coIP experiments. This work was supported by NIH ( CA158112 and CA100632 to J.-P.J.I., GM117437 and CA216134-01 to X.G., GM110174 to B.A.G., GM123336 to J.K., and DK105267 to O.P.-L.) Research funding was also provided by the Van Andel Research Institute through the Van Andel Research Institute-Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by American Association for Cancer Research . The work used the Extreme Science and Engineering Discovery Environment (XSEDE) allocation MCB130049 , which is supported by National Science Foundation ( ACI-1548562 ). J.-P.J.I. is an American Cancer Society Clinical Research professor supported by a generous gift from the F.M. Kirby Foundation . Funding Information: We thank Dr. Roland Dunbrack for providing a superposed set of all CDK kinase structures from the Protein Data Bank. We are grateful to OpenEye Scientific Software (Santa Fe, NM) for providing an academic license for the use of ROCS and OMEGA. We thank Dr. Bassel E. Sawaya for providing CDK9 constructs for the coIP experiments. This work was supported by NIH (CA158112 and CA100632 to J.-P.J.I., GM117437 and CA216134-01 to X.G., GM110174 to B.A.G., GM123336 to J.K., and DK105267 to O.P.-L.) Research funding was also provided by the Van Andel Research Institute through the Van Andel Research Institute-Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by American Association for Cancer Research. The work used the Extreme Science and Engineering Discovery Environment (XSEDE) allocation MCB130049, which is supported by National Science Foundation (ACI-1548562). J.-P.J.I. is an American Cancer Society Clinical Research professor supported by a generous gift from the F.M. Kirby Foundation. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = nov,
day = "15",
doi = "10.1016/j.cell.2018.09.051",
language = "English",
volume = "175",
pages = "1244--1258.e26",
journal = "Cell",
issn = "0092-8674",
number = "5",
}