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The mammalian target ofrapamycin (mTOR) has emerged as an important cancer therapeutic target.Several mTOR inhibitors are currently being tested in cancer clinical trials.Although mTOR inhibitors were shown to improve overall survival among patients with metastatic renal-cell carcinoma, the single agent activity ofmTOR inhibitors has been modest, at best, in most other tumor-types.We are interested in developing strategies for enhancing mTOR-targeted cancer therapy.Both PI3 kinase/Akt and MEK/ERK signaling regulate mTOR axis.However, inhibition of mTOR activates Akt as well as MEK/Akt survival signaling pathways.Moreover, inhibition of mTOR increases elF4E phosphorylation.The paradoxical activation of the aforementioned survival pathways during mTOR inhibition may in turn attenuate mTOR inhibitors anticancer efficacy.Accordingly, prevention or blockage of the activation of these survival signaling pathways induced by mTOR inhibition will enhance mTOR inhibitors anticancer efficacy.