Abstract 2705: AKT inhibition sensitizes tumor cells to rapamycin by enhancing the repressive function of PRS40 on mTORC1/4E-BP1 axis

Abstract

Abstract The mTORC1 inhibitors, rapamycin and its analogs, have been used for the treatment of a variety of cancers, but the clinical performance of these drugs has fallen short of expectations due to only modest efficacy in tumors. The underlying mechanisms of rapamycin resistance remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 shows incomplete inhibition of 4E-BP1 phosphorylation, and is functionally manifest as cap-dependent translation, cell growth and motility. However, treatment with both drugs provides profound effects in vitro and in vivo. Mechanistically, we demonstrate that the combination treatment is required to effectively inhibit PRAS40 phosphorylation on both Ser183 and Thr246 mediated by mTORC1 and AKT respectively, and with the combined treatment, dephosphorylated PRAS40 binding to the raptor/mTOR complex is enhanced, leading to dramatic repression of mTORC1-regulated 4E-BP1 phosphorylation and translation. Knockdown of PRAS40 or 4E-BP1 expression markedly reduces the dependence of tumor cells on AKT/mTORC1 signaling for translational control of cell proliferation, survival and motility. Together, these findings reveal a critical role of PRAS40 as a key integrator of mTORC1 and AKT signaling for the translational regulation of tumor cell growth and motility, and highlight PRAS40 phosphorylation as a potential surrogate marker to evaluate the therapeutic response to mTOR inhibitors. Citation Format: Wenting Mi, Qing Ye, Side Liu, Qing-Bai She. AKT inhibition sensitizes tumor cells to rapamycin by enhancing the repressive function of PRS40 on mTORC1/4E-BP1 axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2705. doi:10.1158/1538-7445.AM2015-2705