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

Institut for Klinisk Medicin

225 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	26
Udgave nummer	6
Sider (fra-til)	909-922
Antal sider	14
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccell.2014.10.019
Status	Udgivet - 8 dec. 2014

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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, bind 26, nr. 6, s. 909-922. https://doi.org/10.1016/j.ccell.2014.10.019

@article{b916eaf46b2440f7b22f35a2ffb7cceb,

title = "Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor",

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.",

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",

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

year = "2014",

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doi = "10.1016/j.ccell.2014.10.019",

language = "English",

volume = "26",

pages = "909--922",

journal = "Cancer Cell",

issn = "1535-6108",

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T1 - Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

AU - Christensen, Camilla L

AU - Kwiatkowski, Nicholas

AU - Abraham, Brian J

AU - Carretero, Julian

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

PY - 2014/12/8

Y1 - 2014/12/8

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

C2 - 25490451

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

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