AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity

Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone. ► Inhibition of PI3K-AKT signaling in tumors activates receptor tyrosine kinases ► Induction is due to relief of feedback inhibition of FOXO-dependent RNA expression ► AKT activates feedback via FOXO- and mTORC1-dependent pathways ► Inhibition of both AKT and induced RTKs is a promising therapeutic strategy