| First Author | Rudalska R | Year | 2014 |
| Journal | Nat Med | Volume | 20 |
| Issue | 10 | Pages | 1138-46 |
| PubMed ID | 25216638 | Mgi Jnum | J:227740 |
| Mgi Id | MGI:5702547 | Doi | 10.1038/nm.3679 |
| Citation | Rudalska R, et al. (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med 20(10):1138-46 |
| abstractText | 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. |
