Phosphatidylinositol 3-kinase and mammalian target of rapamycin (PI3K and mTOR)

Phosphatidylinositol 3-kinase (PI3K) is a family of lipid kinases that phosphorylate phosphoinositides on the 3-position of the inositol ring, generating second messengers essential for signal transduction in cellular growth, proliferation, survival, and metabolism[1][4][5]. The mammalian (or mechanistic) target of rapamycin (mTOR) is a serine/threonine kinase that acts downstream of PI3K, integrating signals from nutrients, growth factors, and cellular energy status to regulate protein synthesis and cell growth[8]. PI3K and mTOR are closely related structurally—mTOR actually contains a kinase domain similar to that of PI3Ks[3]—and they are functionally linked in the PI3K/AKT/mTOR pathway, one of the most important and frequently dysregulated oncogenic signaling cascades in human cancer[2][4][7]. Aberrant activation of this pathway, due to mutations (such as PIK3CA) or loss of regulatory genes (such as PTEN), results in enhanced proliferation, survival, and therapeutic resistance[2][5][7][8]. Both PI3K and mTOR are validated therapeutic targets, with several approved cancer drugs as well as many investigational inhibitors designed to target either or both proteins[5][8].

Other names

PI3K and mTORPI3K/mTORPhosphoinositide 3-kinase and mechanistic target of rapamycinPI3K–mTOR

Inhibition of PI3K blocks generation of phosphatidylinositol-3,4,5-trisphosphate, reducing AKT activation and downstream survival signals[4][5][7]. Inhibition of mTOR blocks downstream effectors (such as S6 kinase, 4EBP1) and protein synthesis, halting cell growth and proliferation[8]. Dual PI3K/mTOR inhibitors block both upstream lipid kinase activity and downstream protein synthesis[5].