Journal
GENES & DEVELOPMENT
Volume 28, Issue 16, Pages 1800-1814Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.244368.114
Keywords
RNAi screen; CDK9; MYC; oncogene addiction; transcription elongation
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Funding
- Ministry of Education of Taiwan
- EMBO Long-Term fellowship
- German Research Foundation (DFG)
- Andrew Seligson Memorial Clinical Fellowship
- [CA008748]
- [CA176671]
- [5U01 CA168409-02]
- [CA013106]
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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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