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Huang, Chun-Hao; Lujambio, Amaia; Zuber, Johannes; Tschaharganeh, Darjus F; Doran, Michael G; Evans, Michael J; Kitzing, Thomas; Zhu, Nan; de Stanchina, Elisa; Sawyers, Charles L; Armstrong, Scott A; Lewis, Jason S; Sherr, Charles J; Lowe, Scott W
Genes & development, 2014-Aug-15, 2014-08-15, 20140815, Volume: 28, Issue: 16Journal Article
One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.
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