The loss and then the reinduction of T308 phosphorylation and AKT action will be the result of those two opposing effects. This can be supported by our data, in cells expressing the AKT S473D mutant, AZD8055 FDA approved HDAC inhibitors causes a rapid monophasic rise in phosphorylation that’s perhaps not preceded by a decline. In comparison, in cells in which relief of RTK feedback is inhibited, AZD8055 causes stable inhibition of phosphorylation of T308 without rebound. In cells in which mTOR kinase inhibitors minimize feedback inhibition of receptor tyrosine kinase resulting in activation of PI3K, the result can be a new steady state in which mTORC1 is potently inhibited and AKT is phosphorylated on T308 however not on the S473 site. That AKT species is triggered and in a position to phosphorylate key substrates within the cell. Whether the activity of AKT monophosphorylated on the T308 site differs from that of AKT phosphorylated on both residues in the range or strength of substrate phosphorylation remains to be identified. Previously, selective neuroendocrine system deletion of mTORC2 activity in MEFs with Rictor and mLST8 knockouts is used to show that phosphorylation of all AKT substrates is mTORC2 independent but that phosphorylation of FOXO proteins depends upon intact mTORC2 activity. Of note, we show here that phosphorylation of multiple AKT substrates including FOXO decreases and then increases with phosphorylation of AKT T308 showing that in this system, AKT T308 phosphorylation will do to stimulate phosphorylation of AKT substrates, including FOXO. The foundation for the different effects of pharmacologic natural product libraries and genetic ablation of mTORC2 inhibition on FOXO phosphorylation is not known, but may have to do with the different cell types found in the studies. Our data show that mTOR kinase inhibition does originally hinder AKT activity, but this inhibition is limited by aid of feedback inhibition of receptor tyrosine kinases, leading to induction of PI3K activity. The induction of PI3K activation probably will be determined by which receptor tyrosine kinases are activated and whether their ligands are present. It’s possible that in a few lineages, feedback reactivation of receptor tyrosine kinases is weak or does occur in contexts in which ligands are not available. In these instances, mTOR kinase inhibition will lead to inhibition of AKT activity in addition to inhibition of mTORC1 activity. In tumors in which mTORC1 inhibition contributes to reduction of RTK feedback, in the steady state, mTORC1 will be inhibited, but AKT, after preliminary inhibition, will be reactivated. Growing evidence suggests that dysregulated activation of onco proteins results in extensive feedback through the entire signaling network.