title: CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Cell and Developmental Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Research Institute of Molecular Pathology, Vienna, 1030, Austria;
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Michael G
authors.initials: MG
authors.lastname: Doran
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Thomas
authors.initials: T
authors.lastname: Kitzing
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Sherr
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Cell and Developmental Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; lowes@mskcc.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015723:Gene Library; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D061805:Transcription Elongation, Genetic / Q000502:physiology*
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9
keywords: CDK9; MYC; RNAi screen; oncogene addiction; transcription elongation