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 (US) |
|---|---|
| Pages (from-to) | 909-922 |
| Number of pages | 14 |
| Journal | Cancer Cell |
| Volume | 26 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jan 1 2014 |
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ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
Cite this
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 journal › Article
}
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.
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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 -