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. Raynal; Benjamin 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

doi:10.1016/j.cell.2018.09.051

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

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 language	English (US)
Pages (from-to)	1244-1258.e26
Journal	Cell
Volume	175
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2018.09.051
State	Published - Nov 15 2018

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2018.09.051

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Zhang, H., Pandey, S., Travers, M., Sun, H., Morton, G., Madzo, J., Chung, W., Khowsathit, J., Perez-Leal, O., Barrero, C. A., Merali, C., Okamoto, Y., Sato, T., Pan, J., Garriga, J., Bhanu, N. V., Simithy, J., Patel, B., Huang, J., ... Issa, J. P. J. (2018). Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell, 175(5), 1244-1258.e26. https://doi.org/10.1016/j.cell.2018.09.051

Zhang, H, Pandey, S, Travers, M, Sun, H, Morton, G, Madzo, J, Chung, W, Khowsathit, J, Perez-Leal, O, Barrero, CA, Merali, C, Okamoto, Y, Sato, T, Pan, J, Garriga, J, Bhanu, NV, Simithy, J, Patel, B, Huang, J, Raynal, NJM, Garcia, BA, Jacobson, MA, Kadoch, C, Merali, S, Zhang, Y, Childers, W, Abou-Gharbia, M, Karanicolas, J, Baylin, SB , Zahnow, CA, Jelinek, J, Graña, X & Issa, JPJ 2018, 'Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer', Cell, vol. 175, no. 5, pp. 1244-1258.e26. https://doi.org/10.1016/j.cell.2018.09.051

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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 = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = nov,

day = "15",

doi = "10.1016/j.cell.2018.09.051",

language = "English (US)",

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T1 - Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

AU - Zhang, Hanghang

AU - Pandey, Somnath

AU - Travers, Meghan

AU - Sun, Hongxing

AU - Morton, George

AU - Madzo, Jozef

AU - Chung, Woonbok

AU - Khowsathit, Jittasak

AU - Perez-Leal, Oscar

AU - Barrero, Carlos A.

AU - Merali, Carmen

AU - Okamoto, Yasuyuki

AU - Sato, Takahiro

AU - Pan, Joshua

AU - Garriga, Judit

AU - Bhanu, Natarajan V.

AU - Simithy, Johayra

AU - Patel, Bela

AU - Huang, Jian

AU - Raynal, Noël J.M.

AU - Garcia, Benjamin A.

AU - Jacobson, Marlene A.

AU - Kadoch, Cigall

AU - Merali, Salim

AU - Zhang, Yi

AU - Childers, Wayne

AU - Abou-Gharbia, Magid

AU - Karanicolas, John

AU - Baylin, Stephen B.

AU - Zahnow, Cynthia A.

AU - Jelinek, Jaroslav

AU - Graña, Xavier

AU - Issa, Jean Pierre J.

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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.

AB - 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.

KW - BRG1

KW - CDK9

KW - DNA methylation

KW - SMARCA4

KW - SWI/SNF

KW - drug development

KW - epigenetic therapy

KW - gene silencing

KW - immunosensitization

KW - kinase inhibitors

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DO - 10.1016/j.cell.2018.09.051

M3 - Article

C2 - 30454645

AN - SCOPUS:85056698270

SN - 0092-8674

VL - 175

SP - 1244-1258.e26

JO - Cell

JF - Cell

IS - 5

ER -

Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

Abstract

Keywords

ASJC Scopus subject areas

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