Baseline Akt phosphorylation was considerably greater in RS cells. Rapamycin also generated a considerably greater increase in Akt phosphorylation in RS Lapatinib clinical trial cells. Furthermore, patients who had a partial response were more likely to have a rise in p Akt T308 with treatment in comparison to patients with stable disease or progression. Rapamycin activates Akt in a number of types. IGF I and insulin-dependent induction of the PI3K/Akt pathway leads to feedback inhibition of signaling due to mTOR/S6K mediated phosphorylation and degradation of IRS 1. Rapamycin induced Akt activation is caused by the increased loss of this negative feedback loop. Nevertheless, rictor containing mTOR complex 2, is involved with Akt phosphorylation on S473. Rictor also regulates the ability of integrin linked kinase to advertise Akt phosphorylation. Reducing rictor expression with rictor siRNA knock down attenuates rapalog induced Akt S473 Messenger RNA (mRNA) phosphorylation, indicating that increases in Akt S473 phosphorylation associated with mTORC1 inhibition are dependent on the presence of rictor. We formerly reported that rapamycin treatment results in rictor dephosphorylation, although rictor was initially reported to lead be a rapamycin insensitive partner of mTOR. It was subsequently demonstrated that rictor T1135 is specifically phosphorylated by mTORC1 dependent kinase. Expression of a phosphorylation site mutant of rictor raises Akt S473 phosphorylation, although this phosphorylation doesn’t influence mTORC2 complex formation or in vitro kinase activity. Thus, rapamycin mediated rictor T1135 dephosphorylation may represent yet another system through which mTORC1 inhibition contributes to feedback activation of Akt signaling. Hence, natural product libraries there may be multiple regulatory links between Akt and mTORC1 dependent signaling, and multiple mechanisms of rapamycin mediated activation of Akt. More over, the result of rapamycin on Akt phosphorylation varies with cell-type. As an example, rapamycin derivatives have already been shown to inhibit Akt signaling by inhibiting mTORC2 formation in acute myeloid leukemia cells both in vivo and in vitro. Further work to determine mechanism of differential regulation of Akt phosphorylation is ongoing. We and others have seen Akt activation in several RS designs. Breuleux et al. Learned p Akt levels at baseline and with treatment with everolimus in 13 cell lines and figured antiproliferative response to everolimus correlates with basal activation of the Akt pathway although not with Akt phosphorylation response following everolimus treatment. Our results in terms of baseline pathway activation are similar, yet in distinction, our data implies that RS cells have a somewhat higher Akt activation with rapamycin treatment potentially recognized as a result of quantitative RPPA approach.