Fig. 1

Schematic diagram of PI3K/Akt/mTOR signaling pathway and relevant PI3K inhibitors. When the growth factors bind to their corresponding RTKs, the regulatory isoform of PI3K (p85) binds to RTKs and relieves its inhibition on the catalytic isoform (p110), leading to the activation of PI3K. PI3K gives rise to the production of the lipid messenger PIP3 from PIP2, which can be reversed by the tumor suppressor PTEN. Subsequently, PIP3 binds to the PH domain of Akt and recruits Akt to the plasma membrane. PDK-1 is also recruited by PIP3 to the plasma membrane through its PH domain, and then phosphorylates Akt at Thr308. Akt is completely activated through phosphorylation at Ser473 by mTORC2 (PDK-2). PHLPP is able to dephosphorylate Akt at Ser473. Activated Akt phosphorylates a variety of downstream pathway molecules to facilitate tumor cell survival, proliferation, migration, invasion and glucose metabolism. The Akt downstream mTORC1 axis also regulates protein synthesis and cell growth. The tumor suppressor TSC1 and TSC2 are two substrates of Akt, and their phosphorylation leads to the blockade of their inhibitory effects on mTORC1. Activated mTORC1 then phosphorylates 4EBP1 and p70 S6 K, resulting in the initiation of protein translation. Activation of mTORC1 also triggers a negative feedback to suppress Akt phosphorylation. Numerous PI3K inhibitors have been developed to target PI3K/Akt/mTOR signaling. Pan-PI3K and isoform-selective PI3K inhibitors suppress the activities of p110 catalytic isoforms, while PI3K/mTOR inhibitors block the activation of both p110 and mTORC1/2