Phosphoinositide 3-kinase–Akt–mTOR pathway (PI3K–Akt–mTOR pathway)

The Phosphoinositide 3-kinase–Akt–mTOR pathway is a central cellular signaling pathway controlling processes such as cell growth, proliferation, survival, metabolism, and migration. Its core elements—PI3K, Akt (protein kinase B), and mTOR (mechanistic target of rapamycin)—receive upstream signals from receptor tyrosine kinases, G protein-coupled receptors, and other cellular sensors. Upon activation, PI3K phosphorylates membrane lipids, creating docking sites for Akt, which is then activated by phosphorylation through PDK1 (at Thr308) and mTORC2 (at Ser473). Activated Akt transduces signals to multiple downstream effectors, including mTOR complexes (mTORC1, mTORC2), which further regulate protein synthesis, autophagy, and survival. Dysregulation of this pathway—via mutations in PIK3CA, AKT, PTEN, or mTOR—leads to oncogenic transformation, tumor progression, therapeutic resistance, and other pathologies. Drugs that inhibit components of the PI3K–Akt–mTOR pathway are under clinical development and approved for certain cancers, though efficacy is limited by pathway complexity, compensatory signaling, and significant toxicity.

Other names

PI3K–Akt pathwayPI3K–Akt–mTOR signaling pathwayPI3K–mTOR pathwayPI3K pathway

Inhibition of PI3K catalytic activity, preventing downstream PIP3 production and subsequent Akt activation Allosteric or ATP-competitive inhibition of Akt, blocking phosphorylation of downstream targets mTORC1 and/or mTORC2 inhibitors leading to reduced protein synthesis, cell growth, and survival Dual PI3K/mTOR inhibition for overcoming feedback activation and resistance mechanisms