In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer Journal Article
| Authors: | 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. |
| Article 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. |
| Keywords: | signal transduction; genetics; sorafenib; antineoplastic agents; carcinoma, hepatocellular; liver neoplasms; antineoplastic agent; mouse; animal; metabolism; animals; mice; map kinase signaling system; protein kinase inhibitor; small interfering rna; rna, small interfering; rna interference; drug resistance; drug screening; drug resistance, neoplasm; xenograft model antitumor assays; mice, inbred c57bl; c57bl mouse; protein kinase inhibitors; nicotinamide; activating transcription factor 2; mitogen activated protein kinase 14; liver neoplasms, experimental; niacinamide; drug effects; phenylurea compounds; carbanilamide derivative; humans; human; male; female; atf2 protein, mouse; analogs and derivatives; antagonists and inhibitors; mitogen-activated protein kinase 14 |
| Journal Title: | Nature Medicine |
| Volume: | 20 |
| Issue: | 10 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-10-01 |
| Start Page: | 1138 |
| End Page: | 1146 |
| Language: | English |
| DOI: | 10.1038/nm.3679 |
| PUBMED: | 25216638 |
| PROVIDER: | scopus |
| PMCID: | PMC4587571 |
| DOI/URL: | |
| Notes: | Export Date: 2 March 2015 -- Source: Scopus |
