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. Author manuscript; available in PMC: 2014 Oct 1.
Published in final edited form as: Clin Cancer Res. 2013 Oct 1;19(19):10.1158/1078-0432.CCR-13-0142. doi: 10.1158/1078-0432.CCR-13-0142

Figure 3.

Figure 3

Feedback signaling following PI3K, AKT, or dual mTORC1/2 inhibition. (A) The baseline status of the PI3K signaling cascade, indicating negative feedback to RTKs such as HER3 and IGF1R, via inactivation of the FOXO transcription factors by AKT. (B) PI3K, AKT, or dual mTORC1/2 inhibitor inactivate AKT, releasing the inhibition of FOXO transcription factors, leading to expression and activation of HER3, IGF1R, and other RTKs, leading to activation of PI3K and AKT activation, and potentially other pathways (i.e. RAS-RAF-MEK-ERK). This effect is delayed in vitro by 24–72 hours or more, and represents a reequilibration of the pathway over time. (C) The addition RTK inhibitors can block the compensatory signaling and induce synergy with PI3K, AKT, and/or dual mTORC1/2 inhibitors.