mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling

TLDR: The adaptive capabilities of oncogenic signaling networks are revealed, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.

Abstract: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin 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 However, inhibition of mTOR kinase also relieves feedback inhibition 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 Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in profound cell death and tumor regression in vivo These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways