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- Title
In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer.
- Authors
Rudalska, Ramona; Dauch, Daniel; Longerich, Thomas; McJunkin, Katherine; Wuestefeld, Torsten; Kang, Tae-Won; Hohmeyer, Anja; Pesic, Marina; Leibold, Josef; von Thun, Anne; Schirmacher, Peter; Zuber, Johannes; Weiss, Karl-Heinz; Powers, Scott; Malek, Nisar P; Eilers, Martin; Sipos, Bence; Lowe, Scott W; Geffers, Robert; Laufer, Stefan
- 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.
- Subjects
RNA interference; ANTINEOPLASTIC agents; LIVER cancer; GENE amplification; MITOGEN-activated protein kinases
- Publication
Nature Medicine, 2014, Vol 20, Issue 10, p1138
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3679