We and the others have partially characterized the reduction of negative feedback induced by modest mTORC1 inhibition with rapamycin or even the effective and selective inhibition of AKT. The are in keeping with a design in which activation of AKT by receptors causes the Oprozomib 935888-69-0 coordinate feedback inhibition of receptor tyrosine kinase signaling and expression by FOXO and mTOR dependent mechanisms. mTOR service causes the down-regulation of IRS1 and other signaling intermediates and inhibition of the HER and Igf-1 R/Insulin receptor tyrosine kinases as well. Inhibition of FOXO transcription factors by AKT dependent phosphorylation downregulates the expression of Insulin receptors, Igf-1 Dtc, and HER3. AKT inhibition checks mTOR, coordinately reduces this feedback, triggers FOXO function, and causes the induction of the expression and activity of HER3, IGF1 R/Insulin receptor and other receptors. Rapamycin Organism relieves feedback differently, inhibition of mTORC1 also causes IRS1 expression and receptor activation and stimulates signaling. Nevertheless, by further activating AKT, FOXO remains inhibited and the receptor mRNAs are not induced. We show here that mTOR kinase inhibition results in a third and more complicated pattern of effects on these feedback pathways, with initial inhibition of AKT activity which then recovers. This is caused by re induction of the phosphorylation of multiple HER kinases, Igf-1 Dhge, insulin receptor and other receptors that is a great deal more marked compared to one seen with rapamycin. This result is likely due to temporary powerful inhibition of AKT activity and to a more complete inhibition of mTORC1 by mTOR kinase inhibitors. This results in an initial induction of both receptor expression and activity by these drugs but only the latter by rapamycin. These findings have important implications for the biology of tumors with deregulated PI3K/AKT/mTOR signaling and for their treatment with inhibitors of aspects of the pathway. One prediction from your data is that certain receptor tyrosine kinases will likely Dabrafenib 1195768-06-9 be downregulated in these tumors until feedback inhibition by AKT or mTOR has been altered by other genetic lesions. These tumors are unlikely to be influenced by these receptors. This is particularly true for IGF1 R, since IGF 1 signaling is powerfully downregulated by multiple AKT or mTOR dependent feedback mechanisms, including downregulation of the expression of their prime substrates, insulin receptor and IGF1 R, IRS1 and IRS2. In tumors treated with inhibitors of the process, the cyst cell reactivates IGF 1 signaling and might survive in a IGF1 R dependent fashion. This may be a general function of those tumors, feedback reactivation of receptor tyrosine kinase signaling may substantially reduce their sensitivity to mTOR kinase inhibitors.