A. PI3K can become active, under physiologic conditions, via upstream RTK signaling and/or RAS. Activation of PI3K leads to downstream signal amplification through AKT and mTOR, resulting in increased protein translation, proliferation and survival. The PI3K/AKT/mTOR signaling axis can regulate its own activity through the negative feedback loops shown, as well as from negative pathway regulators PTEN and NF-1. B. Known nodes within the pathway mutated/hyperactivated in cancer are shown. C. Adaptive signaling in response to PI3K/AKT/mTOR inhibition is shown, resulting in therapy evasion.