Abstract P4-08-02: Reactivation of oncogenic signaling through mTOR inhibitors-induced feedback adaptations.

Abstract

Abstract mTORC1 inhibitors (or rapalogs) relieve feedback inhibition of receptor tyrosine kinases (RTKs) and cause mTORC2-dependent phosphorylation of AKT S473 and activation of AKT kinase and signaling. The relief of feedback inhibition of mTORC2/AKT signaling has been shown to abolish the antitumor activity of rapalogs and has often been proposed as a potential mechanism of resistance to these compounds. mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 complexes have now been developed to circumvent these problems. 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 novel classes of 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, as observed with rapalogs, also relieves feedback inhibition of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT but only at T308, which is 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. We now confirm that the reactivation of AKT signaling is a mechanism of acquired resistance to rapalogs. We observe an induction of phospho-RTKs in rapamycin-resistant cells leading to both AKT and ERK signaling pathway activation enhancing cell survival. Combined inhibition of mTOR and the induced RTKs can prevent AKT reactivation and fully abolishes AKT signaling. These results reveal the adaptive capabilities of oncogenic signaling networks, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-02.