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

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

Author information

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.

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.

PMID:
25216638
PMCID:
PMC4587571
DOI:
10.1038/nm.3679
[Indexed for MEDLINE]
Free PMC Article

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