Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor
Author(s)Christensen, Camilla L.; 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.; Wong, Kwok-Kin; Kwiatkowski, Nick; Abraham, Brian Joseph; Young, Richard A; ... Show more Show less
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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.
DepartmentBroad Institute of MIT and Harvard; Massachusetts Institute of Technology. Department of Biology
Christensen, Camilla L. et al. “Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor.” Cancer Cell 26, no. 6 (December 2014): 909–922. © 2014 Elsevier Inc
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