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

Rudalska, R., Dauch, D., Longerich, T., McJunkin, K., Wuestefeld, T., Kang, T. W., Hohmeyer, A., Pesic, M., Leibold, J., von Thun, A., Schirmacher, P., Zuber, J., Weiss, K. H., Powers, S., Malek, N.P., Eilers, M., Sipos, B., Lowe, S. W., Geffers, R., Laufer, S., Zender, L. (September 2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nature Medicine, 20 (10). pp. 1138-1146. ISSN 1078-8956

URL: http://www.ncbi.nlm.nih.gov/pubmed/25216638
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 (p38alpha) 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
diseases & disorders > cancer > drugs and therapies > chemoresistance
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > liver cancer
CSHL Authors:
Communities: CSHL labs > Powers lab
Watson School > Publications
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 14 September 2014
Date Deposited: 24 Sep 2014 14:59
Last Modified: 15 Oct 2015 15:38
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30814

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