title: In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer.
abstract: In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38α) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.
authors.affiliation: 1] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. [2].
authors.forename: Ramona
authors.initials: R
authors.lastname: Rudalska
authors.affiliation: 1] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. [2].
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: The Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: McJunkin
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.affiliation: 1] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. [2] Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kang
authors.affiliation: 1] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. [2] Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hohmeyer
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Pesic
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Leibold
authors.affiliation: 1] Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany. [2] Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: von Thun
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Weiss
authors.affiliation: Cancer Genome Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Scott
authors.identifier: 0000000284031861
authors.initials: S
authors.lastname: Powers
authors.affiliation: Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: 1] Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany. [2] Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Martin
authors.identifier: 0000000203766533
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Institute of Pathology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Bence
authors.identifier: 0000000273113343
authors.initials: B
authors.lastname: Sipos
authors.affiliation: 1] Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Howard Hughes Medical Institute, New York, New York, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, University of Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.affiliation: 1] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. [2] Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D051698:Activating Transcription Factor 2; D000970:Antineoplastic Agents; C497106:Atf2 protein, mouse; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D009536:Niacinamide; D000077157:Sorafenib; D048308:Mitogen-Activated Protein Kinase 14