In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer

Ramona Rudalska; Daniel Dauch; Thomas Longerich; Katherine McJunkin; Torsten Wuestefeld; Tae-Won Kang; Anja Hohmeyer; Marina Pesic; Josef Leibold; Anne von Thun; Peter Schirmacher; Johannes Zuber; Karl-Heinz Weiss; Scott Powers; Nisar P Malek; Martin Eilers; Bence Sipos; Scott W Lowe; Robert Geffers; Stefan Laufer; Lars Zender

doi:10.1038/nm.3679

In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer

Nat Med. 2014 Oct;20(10):1138-46. doi: 10.1038/nm.3679. Epub 2014 Sep 14.

Authors

Ramona Rudalska¹, Daniel Dauch¹, Thomas Longerich², Katherine McJunkin³, Torsten Wuestefeld⁴, Tae-Won Kang⁵, Anja Hohmeyer⁵, Marina Pesic⁴, Josef Leibold⁴, Anne von Thun⁶, Peter Schirmacher², Johannes Zuber⁷, Karl-Heinz Weiss⁸, Scott Powers⁹, Nisar P Malek¹⁰, Martin Eilers⁶, Bence Sipos¹¹, Scott W Lowe¹², Robert Geffers¹³, Stefan Laufer¹⁴, Lars Zender⁵

Affiliations

¹ 1] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. [2].
² Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
³ The Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
⁴ Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
⁵ 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.
⁶ 1] Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany. [2] Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
⁷ Research Institute of Molecular Pathology, Vienna, Austria.
⁸ Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
⁹ Cancer Genome Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
¹⁰ Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
¹¹ Institute of Pathology, University of Tuebingen, Tuebingen, Germany.
¹² 1] Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Howard Hughes Medical Institute, New York, New York, USA.
¹³ Helmholtz Centre for Infection Research, Braunschweig, Germany.
¹⁴ Department of Pharmaceutical and Medicinal Chemistry, University of Tuebingen, Tuebingen, Germany.

PMID: 25216638
PMCID: PMC4587571
DOI: 10.1038/nm.3679

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 2 / metabolism
Animals
Antineoplastic Agents / pharmacology*
Carcinoma, Hepatocellular / drug therapy
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Drug Resistance, Neoplasm / genetics
Female
Humans
Liver Neoplasms / drug therapy
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms, Experimental / drug therapy*
Liver Neoplasms, Experimental / genetics*
Liver Neoplasms, Experimental / metabolism
MAP Kinase Signaling System / drug effects
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / genetics*
Mitogen-Activated Protein Kinase 14 / metabolism
Niacinamide / analogs & derivatives*
Niacinamide / pharmacology
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / pharmacology
RNA Interference
RNA, Small Interfering / genetics
Signal Transduction
Sorafenib
Xenograft Model Antitumor Assays

Substances

Activating Transcription Factor 2
Antineoplastic Agents
Atf2 protein, mouse
Phenylurea Compounds
Protein Kinase Inhibitors
RNA, Small Interfering
Niacinamide
Sorafenib
Mitogen-Activated Protein Kinase 14

Abstract

Publication types

MeSH terms

Substances

Grants and funding