RS cells also had greater inhibition of mTOR signaling, thus the greater increase in Akt phosphorylation in RS cells might be owing to a greater inhibition of S6K with subsequent greater feedback loop activation. O Reilly et al. have reported that feedback loop initial happened not only in vitro, but additionally in vivo, in patients treated on a Phase I trial of everolimus. Cloughesy et al. compared p PRAS40 like a surrogate for Akt activation in major glioblastoma samples and in recurrent tumors which were treated with one week of rapamycin before surgery. People who’d higher g PRAS40 to the second surgical test, had a shorter time toprogression. Our information from the Phase II trial of everolimus based treatment for neuroendocrine tumors where we received pre treatment and on treatment examples implies that p Akt increases more in responders when compared with non responders. Further work is necessary to determine the mechanism though which transfer RNA (tRNA) specific cell lines/tumors have greater rapamycininduced Akt activation than others. Our exploratory results suggest that this at least partly could be due to a greater repression of the axis. Our in vitro and clinical data taken together suggest that rapamycin induced Akt phosphorylation isn’t a marker of rapamycin resistance. Therefore, it’s likely that feedback loop Akt activation does not overcome rapamycin when mTORC1 signaling is the primary oncogenic driver induced growth inhibition. Though feedback cycle activation of Akt is not a sign of resistance to allosteric mTOR inhibitors, this Akt activation might still control the antitumor efficacy of rapamycin and analogs. Ways to prevent Akt activation, including usage of inhibitors of upstream signaling, are increasingly being pursued. Preclinically, combinations of rapamycin and IGFR inhibitors have been shown to have additive anti-tumor effects, and decrease Foretinib c-Met inhibitor feedback loop service. Indeed, this mixture is being actively pursued in clinical trials. In addition, clinical studies are ongoing to test the safety and effectiveness of targeting the path with mTOR kinase inhibitors that will inhibit mTORC1 and as well as mTORC2, or with double PI3K/mTOR inhibitors. Additionally, rapalog treatment has been associated with activation of MAPK signaling, therefore dual targeting of PI3K/mTOR signaling and MAPK signaling can also be being explored clinically. Lately, inhibition of Akt with small molecule inhibitors have been shown to improve HER3 expression/signaling, and mixed targeting of HER3 and Akt was shown to enhance efficacy. Therefore feedback cycle activation is clearly not just a phenomenon limited to allosteric mTOR inhibitors. Assessment of adaptive or survival responses to new targeted therapies should be pursued as a technique for design logical combinatorial therapies.