Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

Camilla L Christensen; Nicholas Kwiatkowski; Brian J Abraham; Julian Carretero; Fatima Al-Shahrour; Tinghu Zhang; Edmond Chipumuro; Grit S Herter-Sprie; Esra A Akbay; Abigail Altabef; Jianming Zhang; Takeshi Shimamura; Marzia Capelletti; Jakob B Reibel; Jillian D Cavanaugh; Peng Gao; Yan Liu; Signe Regner Michaelsen; Hans S Poulsen; Amir R Aref; David A Barbie; James E Bradner; Rani E George; Nathanael S Gray; Richard A Young; Kwok-Kin Wong

doi:10.1016/j.ccell.2014.10.019

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

Camilla L Christensen, Nicholas Kwiatkowski, Brian J Abraham, Julian Carretero, Fatima Al-Shahrour, Tinghu Zhang, Edmond Chipumuro, Grit S Herter-Sprie, Esra A Akbay, Abigail Altabef, Jianming Zhang, Takeshi Shimamura, Marzia Capelletti, Jakob B Reibel, Jillian D Cavanaugh, Peng Gao, Yan Liu, Signe Regner Michaelsen, Hans S Poulsen, Amir R ArefDavid A Barbie, James E Bradner, Rani E George, Nathanael S Gray, Richard A Young, Kwok-Kin Wong

Department of Clinical Medicine

225 Citations (Scopus)

Abstract

Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.

Original language	English
Journal	Cancer Cell
Volume	26
Issue number	6
Pages (from-to)	909-922
Number of pages	14
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccell.2014.10.019
Publication status	Published - 8 Dec 2014

Keywords

Animals
Antineoplastic Agents
Cell Line, Tumor
Cyclin-Dependent Kinases
Enzyme Inhibitors
Gene Expression Regulation, Neoplastic
High-Throughput Screening Assays
Humans
Lung Neoplasms
Mice
Molecular Sequence Data
Neoplasms, Experimental
Sequence Analysis, DNA
Small Cell Lung Carcinoma
Transcription Factors
Transcription, Genetic
Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2014.10.019

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Christensen, C. L., Kwiatkowski, N., Abraham, B. J., Carretero, J., Al-Shahrour, F., Zhang, T., Chipumuro, E., Herter-Sprie, G. S., Akbay, E. A., Altabef, A., Zhang, J., Shimamura, T., Capelletti, M., Reibel, J. B., Cavanaugh, J. D., Gao, P., Liu, Y., Michaelsen, S. R., Poulsen, H. S., ... Wong, K.-K. (2014). Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor. Cancer Cell, 26(6), 909-922. https://doi.org/10.1016/j.ccell.2014.10.019

Christensen, CL, Kwiatkowski, N, Abraham, BJ, Carretero, J, Al-Shahrour, F, Zhang, T, Chipumuro, E, Herter-Sprie, GS, Akbay, EA, Altabef, A, Zhang, J, Shimamura, T, Capelletti, M, Reibel, JB, Cavanaugh, JD, Gao, P, Liu, Y, Michaelsen, SR, Poulsen, HS, Aref, AR, Barbie, DA, Bradner, JE, George, RE, Gray, NS, Young, RA & Wong, K-K 2014, 'Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor', Cancer Cell, vol. 26, no. 6, pp. 909-922. https://doi.org/10.1016/j.ccell.2014.10.019

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abstract = "Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.",

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AU - Kwiatkowski, Nicholas

AU - Abraham, Brian J

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AU - Al-Shahrour, Fatima

AU - Zhang, Tinghu

AU - Chipumuro, Edmond

AU - Herter-Sprie, Grit S

AU - Akbay, Esra A

AU - Altabef, Abigail

AU - Zhang, Jianming

AU - Shimamura, Takeshi

AU - Capelletti, Marzia

AU - Reibel, Jakob B

AU - Cavanaugh, Jillian D

AU - Gao, Peng

AU - Liu, Yan

AU - Michaelsen, Signe Regner

AU - Poulsen, Hans S

AU - Aref, Amir R

AU - Barbie, David A

AU - Bradner, James E

AU - George, Rani E

AU - Gray, Nathanael S

AU - Young, Richard A

AU - Wong, Kwok-Kin

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N2 - Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.

AB - Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.

KW - Animals

KW - Antineoplastic Agents

KW - Cell Line, Tumor

KW - Cyclin-Dependent Kinases

KW - Enzyme Inhibitors

KW - Gene Expression Regulation, Neoplastic

KW - High-Throughput Screening Assays

KW - Humans

KW - Lung Neoplasms

KW - Mice

KW - Molecular Sequence Data

KW - Neoplasms, Experimental

KW - Sequence Analysis, DNA

KW - Small Cell Lung Carcinoma

KW - Transcription Factors

KW - Transcription, Genetic

KW - Xenograft Model Antitumor Assays

U2 - 10.1016/j.ccell.2014.10.019

DO - 10.1016/j.ccell.2014.10.019

M3 - Journal article

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SN - 1535-6108

VL - 26

SP - 909

EP - 922

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

Abstract

Keywords

UN SDGs

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