We have now found that the particular mTOR kinase inhibitor AZD8055 is an efficient inhibitor of both mTORC2 and mTORC1 activity but has complicated effects on AKT signaling. The mTOR kinase substrates AKT S473, 4E BP1 and S6K were maximally dephosphorylated in response to 75mg/kg of AZD8055. At this dose, there is a concomitant induction of the EGFR, HER2, HER3 and IGF 1/IR receptors and ERK phosphorylation. Bortezomib clinical trial In mice, we have found that the regime of AZD8055 that’s best for antitumor therapy is 75mg/kg, three times per week. In BT 474 xenografts treated using a single dose of 75mg/kg of AZD8055, we noticed that AZD8055 effectively inhibited the phosphorylation of mTORC2 and mTORC1 substrates for no less than 24 hours, however the effect was largely passed by 48 hours. As noticed in tissue culture studies, phosphorylation of AKT T308 and the AKT substrates GSK3 N, FOXO1/3, and PRAS40 were initially restricted and fall in parallel with that of the mTOR kinase substrates. Nevertheless, we observed a subsequent increase in their phosphorylation eight hours after drug addition. Induction of phosphorylation of the EGFR, HER2 and HER3 also does occur in vivo at four hours. The phosphorylation of Organism HER2 and EGFR however not HER3 drop after sixteen hours of drug exposure, after reactivation of AKT signaling. Of notice, AKT T308 phosphorylation remains elevated at one day despite loss of HER2 phosphorylation. This means that PI3K activity remains elevated, possibly via activation of other HER3 or other receptors. In sum, the data claim that serious inhibition of mTOR kinase in vivo leads to a new steady state with chronic inhibition of mTORC1, activated AKT phosphorylated on T308 however not S473, and enough PI3K activation to support T308 phosphorylation. To test whether inhibition of reactivated HER kinases sensitized the tumors to mTOR kinase inhibition, we considered the results of mixing AZD8055 with lapatinib about the expansion of BT 474 xenografts. We used a low-dose of lapatinib administered three times weekly that had Imatinib ic50 no anti-tumor activity as a way to differentiate sensitization of the tumor to mTOR kinase inhibition from additive activity of both drugs when administered alone. Long-term AZD8055 therapy causes complete arrest of tumefaction growth with little if any evidence for regression. After eleven days of therapy, the tumors started to re grow, but more slowly compared to controls. In comparison, combined treatment with lapatinib and AZD8055 caused chronic inhibition of growth over three months of treatment and was connected with thirty five percent regression of the tumor. AKT and mTOR are key enzymes controlling important cellular processes including metabolism and cellular growth, both have already been demonstrated to determine the activity of the other.