Abstract LB-20: mTOR kinase inhibition relieves feedback suppression of receptor tyrosine kinase leading to a biphasic regulation of AKT signaling in breast cancer cells

Abstract

Abstract Activation of mitogenic signaling by receptor tyrosine kinases (RTKs) is regulated by negative feedback. Feedback is in part mediated by mTORC1/S6K dependent downregulation of IRS proteins which downregulate IGF/insulin receptor signaling. We have found that mTORC1 inhibitors or rapalogs relieve feedback inhibition of receptor tyrosine kinases and cause mTORC2-dependent phosphorylation of AKT S473 leading to activation of AKT kinase and signaling. This relief of feedback inhibition of mTORC2/AKT signaling has been associated with the limited clinical efficacy of these compounds. mTOR kinase inhibitors have now been developed to circumvent these problems; they block mTORC1 and mTORC2 and thus do not cause the mTORC2-dependent activation of AKT observed with the mTORC1 inhibitors. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473 dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. Inhibition of mTOR kinase also relieves feedback suppression of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound inhibition of mTORC1 and accumulation of activated AKT phosphorylated on T308 but not S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regressions in vivo. These results highlight the possible need for combinatorial approaches to block feedback-regulated pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-20. doi:1538-7445.AM2012-LB-20