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
N1 - Funding Information:
This work was supported by a Post-Doctoral Fellowship (R56-A3106-12-S2) from the Danish Cancer Society (C.L.C.), Deutsche Forschungsgemeinschaft (HE6897/1-1) (G.S.H.-S.), National Institutes of Health grants CA122794, CA140594, CA163896, CA166480, CA154303, and CA120964 (K.-K.W.), grant R01 CA179483-01A1 (N.S.G.), the Thoracic Foundation (K.-K.W.), the Susan Spooner Foundation (K.-K.W.). This work was also supported by the Bridge Project (K.-K.W., N.S.G., and R.A.Y.), a collaboration between The Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center (DF/HCC). R.A.Y., N.S.G., and J.E.B. are founders and equity holders in Syros, which has licensed the CDK7 intellectual property from the Dana-Farber Cancer Institute. N.K., T.Z., and N.S.G. are inventors on a patent application covering THZ1.
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.
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U2 - 10.1016/j.ccell.2014.10.019
DO - 10.1016/j.ccell.2014.10.019
M3 - Article
C2 - 25490451
AN - SCOPUS:84919495606
VL - 26
SP - 909
EP - 922
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -