Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor Journal Article

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Authors: 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.; Aref, A. R.; Barbie, D. A.; Bradner, J. E.; George, R. E.; Gray, N. S.; Young, R. A.; Wong, K. K.
Article 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.
Journal Title: Cancer cell
Volume: 26
Issue: 6
ISSN: 1878-3686; 1535-6108
Publisher: Elsevier Inc  
Journal Place: United States
Date Published: 2014
Start Page: 909
End Page: 922
Language: eng
DOI/URL:

10.1016/j.ccell.2014.10.019
Notes: LR: 20150401; CI: Copyright (c) 2014; GEO/GSE62614; GR: CA120964/CA/NCI NIH HHS/United States; GR: CA122794/CA/NCI NIH HHS/United States; GR: CA140594/CA/NCI NIH HHS/United States; GR: CA154303/CA/NCI NIH HHS/United States; GR: CA163896/CA/NCI NIH HHS/United States; GR: CA166480/CA/NCI NIH HHS/United States; GR: P01 CA154303/CA/NCI NIH HHS/United States; GR: R01 CA122794/CA/NCI NIH HHS/United States; GR: R01 CA140594/CA/NCI NIH HHS/United States; GR: R01 CA163896/CA/NCI NIH HHS/United States; GR: R01 CA166480/CA/NCI NIH HHS/United States; GR: R01 CA179483/CA/NCI NIH HHS/United States; GR: R01 CA179483-01A1/CA/NCI NIH HHS/United States; JID: 101130617; 0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Transcription Factors); EC 2.7.11.22 (Cyclin-Dependent Kinases); CIN: Cancer Cell. 2014 Dec 8;26(6):783-4. PMID: 25490443; EIN: Cancer Cell. 2015 Jan 12;27(1):149; NIHMS640422; OID: NLM: NIHMS640422 [Available on 12/08/15]; OID: NLM: PMC4261156 [Available on 12/08/15]; PMCR: 2015/12/08 00:00; 2014/06/25 [received]; 2014/10/03 [revised]; 2014/10/28 [accepted]; ppublish