Abstract LB-125: Snail determines the efficacy of mTOR-targeted therapies by transcriptional repression of 4E-BP1

Abstract

Abstract 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 effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression in cancer has been linked to malignant progression and poor prognosis. However, the molecular mechanism(s) by which 4E-BP1 is downregulated in cancer remain largely unknown. Here, we identify Snail as a novel repressor of 4E-BP1 expression that can be exploited to alter mTOR-targeted therapies. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Mechanistically, we show that Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly inhibits 4E-BP1 expression, and promotes cap-dependent translation and resistance to the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic depletion of Snail restores 4E-BP1 expression and sensitizes cancer cells to mTOR inhibition by enhancing the translation-repressive function of 4E-BP1 on cell proliferation and tumor growth. Thus, our findings reveal a critical role for Snail in determining the therapeutic response to mTOR kinase inhibitors, and suggest that Snail may be a potential marker for predicting the efficacy of mTOR-target therapies in the clinic. Moreover, our work highlights the importance of combining Snail inhibition with mTOR kinase inhibitors for the treatment of tumors in which Snail overexpression occurs with reduced 4E-BP1 expression. Citation Format: Jun Wang, Qing Ye, Yubin Guo, Yanan Cao, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, B. Mark Evers, Qing-Bai She. Snail determines the efficacy of mTOR-targeted therapies by transcriptional repression of 4E-BP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2017-LB-125