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 R. Michaelsen, Hans S. Poulsen, Amir R. Aref & 6 others David A. Barbie, James E. Bradner, Rani E. George, Nathanael S. Gray, Richard A. Young, Kwok Kin Wong

Research output: Contribution to journalArticle

146 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 languageEnglish (US)
Pages (from-to)909-922
Number of pages14
JournalCancer Cell
Volume26
Issue number6
DOIs
StatePublished - Jan 1 2014

Fingerprint

Small Cell Lung Carcinoma
Transcription Factors
Small Molecule Libraries
Proto-Oncogenes
Cyclin-Dependent Kinases
Drug Delivery Systems
Down-Regulation
Pharmacology
Mortality
Therapeutics
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Christensen, C. L., Kwiatkowski, N., Abraham, B. J., Carretero, J., Al-Shahrour, F., Zhang, T., ... 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

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor. / Christensen, Camilla L.; Kwiatkowski, Nicholas; Abraham, Brian J.; Carretero, Julian; Al-Shahrour, Fatima; Zhang, Tinghu; Chipumuro, Edmond; Herter-Sprie, Grit S.; Akbay, Esra A.; Altabef, Abigail; Zhang, Jianming; Shimamura, Takeshi; Capelletti, Marzia; Reibel, Jakob B.; Cavanaugh, Jillian D.; Gao, Peng; Liu, Yan; Michaelsen, Signe R.; Poulsen, Hans S.; Aref, Amir R.; Barbie, David A.; Bradner, James E.; George, Rani E.; Gray, Nathanael S.; Young, Richard A.; Wong, Kwok Kin.

In: Cancer Cell, Vol. 26, No. 6, 01.01.2014, p. 909-922.

Research output: Contribution to journalArticle

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, KK 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
Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T et al. Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor. Cancer Cell. 2014 Jan 1;26(6):909-922. https://doi.org/10.1016/j.ccell.2014.10.019
Christensen, Camilla L. ; Kwiatkowski, Nicholas ; Abraham, Brian J. ; Carretero, Julian ; Al-Shahrour, Fatima ; Zhang, Tinghu ; Chipumuro, Edmond ; Herter-Sprie, Grit S. ; Akbay, Esra A. ; Altabef, Abigail ; Zhang, Jianming ; Shimamura, Takeshi ; Capelletti, Marzia ; Reibel, Jakob B. ; Cavanaugh, Jillian D. ; Gao, Peng ; Liu, Yan ; Michaelsen, Signe R. ; Poulsen, Hans S. ; Aref, Amir R. ; Barbie, David A. ; Bradner, James E. ; George, Rani E. ; Gray, Nathanael S. ; Young, Richard A. ; Wong, Kwok Kin. / Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor. In: Cancer Cell. 2014 ; Vol. 26, No. 6. pp. 909-922.
@article{90f2bf9969af47d3a607f7b6d70abb07,
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.",
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 R.} 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 Wong, {Kwok Kin}",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.ccell.2014.10.019",
language = "English (US)",
volume = "26",
pages = "909--922",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

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 R.

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 - 2014/1/1

Y1 - 2014/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84919495606&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919495606&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2014.10.019

DO - 10.1016/j.ccell.2014.10.019

M3 - Article

VL - 26

SP - 909

EP - 922

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 6

ER -