CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

Hua Zhang; Camilla L. Christensen; Ruben Dries; Matthew G. Oser; Jiehui Deng; Brian Diskin; Fei Li; Yuanwang Pan; Xuzhu Zhang; Yandong Yin; Eleni Papadopoulos; Val Pyon; Cassandra Thakurdin; Nicholas Kwiatkowski; Kandarp Jani; Alexandra R. Rabin; Dayanne M. Castro; Ting Chen; Heather Silver; Qingyuan Huang; Mirna Bulatovic; Catríona M. Dowling; Belen Sundberg; Alan Leggett; Michela Ranieri; Han Han; Shuai Li; Annan Yang; Kristen E. Labbe; Christina Almonte; Vladislav O. Sviderskiy; Max Quinn; Jack Donaghue; Eric S. Wang; Tinghu Zhang; Zhixiang He; Vamsidhar Velcheti; Peter S. Hammerman; Gordon J. Freeman; Richard Bonneau; William G. Kaelin; Kate D. Sutherland; Ariena Kersbergen; Andrew J. Aguirre; Guo Cheng Yuan; Eli Rothenberg; George Miller; Nathanael S. Gray; Kwok Kin Wong

doi:10.1016/j.ccell.2019.11.003

CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

Hua Zhang, Camilla L. Christensen, Ruben Dries, Matthew G. Oser, Jiehui Deng, Brian Diskin, Fei Li, Yuanwang Pan, Xuzhu Zhang, Yandong Yin, Eleni Papadopoulos, Val Pyon, Cassandra Thakurdin, Nicholas Kwiatkowski, Kandarp Jani, Alexandra R. Rabin, Dayanne M. Castro, Ting Chen, Heather Silver, Qingyuan HuangMirna Bulatovic, Catríona M. Dowling, Belen Sundberg, Alan Leggett, Michela Ranieri, Han Han, Shuai Li, Annan Yang, Kristen E. Labbe, Christina Almonte, Vladislav O. Sviderskiy, Max Quinn, Jack Donaghue, Eric S. Wang, Tinghu Zhang, Zhixiang He, Vamsidhar Velcheti, Peter S. Hammerman, Gordon J. Freeman, Richard Bonneau, William G. Kaelin, Kate D. Sutherland, Ariena Kersbergen, Andrew J. Aguirre, Guo Cheng Yuan, Eli Rothenberg, George Miller, Nathanael S. Gray, Kwok Kin Wong

Research output: Contribution to journal › Article

Abstract

Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.

Original language	English (US)
Pages (from-to)	37-54.e9
Journal	Cancer Cell
Volume	37
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2019.11.003
State	Published - Jan 13 2020

Keywords

CDK7
YKL-5-124
anti-tumor immunity
cell cycle
genome instability
immune checkpoint blockade
immunotherapy
replication stress
single-cell analysis
small cell lung cancer

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Zhang, H., Christensen, C. L., Dries, R., Oser, M. G., Deng, J., Diskin, B., Li, F., Pan, Y., Zhang, X., Yin, Y., Papadopoulos, E., Pyon, V., Thakurdin, C., Kwiatkowski, N., Jani, K., Rabin, A. R., Castro, D. M., Chen, T., Silver, H., ... Wong, K. K. (2020). CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. Cancer Cell, 37(1), 37-54.e9. https://doi.org/10.1016/j.ccell.2019.11.003

CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. / Zhang, Hua; Christensen, Camilla L.; Dries, Ruben; Oser, Matthew G.; Deng, Jiehui; Diskin, Brian; Li, Fei; Pan, Yuanwang; Zhang, Xuzhu; Yin, Yandong; Papadopoulos, Eleni; Pyon, Val; Thakurdin, Cassandra; Kwiatkowski, Nicholas; Jani, Kandarp; Rabin, Alexandra R.; Castro, Dayanne M.; Chen, Ting; Silver, Heather; Huang, Qingyuan; Bulatovic, Mirna; Dowling, Catríona M.; Sundberg, Belen; Leggett, Alan; Ranieri, Michela; Han, Han; Li, Shuai; Yang, Annan; Labbe, Kristen E.; Almonte, Christina; Sviderskiy, Vladislav O.; Quinn, Max; Donaghue, Jack; Wang, Eric S.; Zhang, Tinghu; He, Zhixiang; Velcheti, Vamsidhar; Hammerman, Peter S.; Freeman, Gordon J.; Bonneau, Richard; Kaelin, William G.; Sutherland, Kate D.; Kersbergen, Ariena; Aguirre, Andrew J.; Yuan, Guo Cheng; Rothenberg, Eli; Miller, George; Gray, Nathanael S.; Wong, Kwok Kin.

In: Cancer Cell, Vol. 37, No. 1, 13.01.2020, p. 37-54.e9.

Research output: Contribution to journal › Article

Zhang, H, Christensen, CL, Dries, R, Oser, MG, Deng, J, Diskin, B, Li, F, Pan, Y, Zhang, X, Yin, Y, Papadopoulos, E, Pyon, V, Thakurdin, C, Kwiatkowski, N, Jani, K, Rabin, AR, Castro, DM, Chen, T, Silver, H, Huang, Q, Bulatovic, M, Dowling, CM, Sundberg, B, Leggett, A, Ranieri, M, Han, H, Li, S, Yang, A, Labbe, KE, Almonte, C, Sviderskiy, VO, Quinn, M, Donaghue, J, Wang, ES, Zhang, T, He, Z, Velcheti, V, Hammerman, PS, Freeman, GJ, Bonneau, R, Kaelin, WG, Sutherland, KD, Kersbergen, A, Aguirre, AJ, Yuan, GC, Rothenberg, E, Miller, G, Gray, NS & Wong, KK 2020, 'CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer', Cancer Cell, vol. 37, no. 1, pp. 37-54.e9. https://doi.org/10.1016/j.ccell.2019.11.003

Zhang, Hua ; Christensen, Camilla L. ; Dries, Ruben ; Oser, Matthew G. ; Deng, Jiehui ; Diskin, Brian ; Li, Fei ; Pan, Yuanwang ; Zhang, Xuzhu ; Yin, Yandong ; Papadopoulos, Eleni ; Pyon, Val ; Thakurdin, Cassandra ; Kwiatkowski, Nicholas ; Jani, Kandarp ; Rabin, Alexandra R. ; Castro, Dayanne M. ; Chen, Ting ; Silver, Heather ; Huang, Qingyuan ; Bulatovic, Mirna ; Dowling, Catríona M. ; Sundberg, Belen ; Leggett, Alan ; Ranieri, Michela ; Han, Han ; Li, Shuai ; Yang, Annan ; Labbe, Kristen E. ; Almonte, Christina ; Sviderskiy, Vladislav O. ; Quinn, Max ; Donaghue, Jack ; Wang, Eric S. ; Zhang, Tinghu ; He, Zhixiang ; Velcheti, Vamsidhar ; Hammerman, Peter S. ; Freeman, Gordon J. ; Bonneau, Richard ; Kaelin, William G. ; Sutherland, Kate D. ; Kersbergen, Ariena ; Aguirre, Andrew J. ; Yuan, Guo Cheng ; Rothenberg, Eli ; Miller, George ; Gray, Nathanael S. ; Wong, Kwok Kin. / CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. In: Cancer Cell. 2020 ; Vol. 37, No. 1. pp. 37-54.e9.

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title = "CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer",

abstract = "Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.",

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AU - Dries, Ruben

AU - Oser, Matthew G.

AU - Deng, Jiehui

AU - Diskin, Brian

AU - Li, Fei

AU - Pan, Yuanwang

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AU - Kwiatkowski, Nicholas

AU - Jani, Kandarp

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AU - Castro, Dayanne M.

AU - Chen, Ting

AU - Silver, Heather

AU - Huang, Qingyuan

AU - Bulatovic, Mirna

AU - Dowling, Catríona M.

AU - Sundberg, Belen

AU - Leggett, Alan

AU - Ranieri, Michela

AU - Han, Han

AU - Li, Shuai

AU - Yang, Annan

AU - Labbe, Kristen E.

AU - Almonte, Christina

AU - Sviderskiy, Vladislav O.

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AU - Donaghue, Jack

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AU - He, Zhixiang

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AU - Kaelin, William G.

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AU - Aguirre, Andrew J.

AU - Yuan, Guo Cheng

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