LAUSR

The mTOR inhibitors, including the second generation of mTOR kinase inhibitors, for cancer treatment have been evaluated in clinical trials, but their overall activity as monotherapy is limited. The cap-dependent translation repressor, 4E-BP1, is an important downstream effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors. However, the molecular mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here, we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to block the transcription of the 4E-BP1 gene. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes the formation of the eIF4F translation initiation complex for active translation in polysomes, and reduces the antiproliferative effect of mTOR kinase inhibitors. Conversely, genetic disruption of Snail or pharmacologic inhibition of Snail activity using the Snail co-repressor HDAC inhibitors restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Together, our findings reveal a novel oncogenic function of Snail in mTOR/4E-BP1-mediated translational control of tumorigenesis, and provide a rationale for targeting Snail to improve mTOR-targeted therapies. Citation Format: Qing Ye, Jun Wang, Yanan Cao, Yubin Guo, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, Hsin-Sheng Yang, Binhua Zhou, Bernard M. Evers, Qing-Bai She. Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5894.