Phosphatidylinositol 3-kinase-Protein kinase B signaling pathway (PI3K-Akt pathway)

The Phosphatidylinositol 3-kinase (PI3K)-Protein kinase B (Akt) signaling pathway is a critical intracellular cascade that regulates essential cellular processes, including survival, growth, proliferation, and metabolism [9, 22]. It is typically activated by the binding of extracellular ligands to receptor tyrosine kinases (RTKs) or G-protein-coupled receptors (GPCRs), leading to the recruitment of PI3K to the plasma membrane [6, 19]. PI3K then catalyzes the formation of phosphatidylinositol-3,4,5-trisphosphate (PIP3), which serves as a docking site for Akt and its activator PDK1 [1, 22]. Once fully activated, Akt phosphorylates a wide array of downstream effectors, such as mTOR and FOXO, to promote cell cycle progression and inhibit pro-apoptotic signals [9, 19]. This pathway is one of the most frequently dysregulated networks in human cancer, often through gain-of-function mutations in PIK3CA or loss of the tumor suppressor PTEN [5, 15]. Such alterations drive constitutive signaling that supports tumor growth, angiogenesis, and resistance to conventional therapies [10, 16]. Numerous drugs have been developed to target this pathway, including isoform-specific PI3K inhibitors (e.g., alpelisib), pan-PI3K inhibitors, and inhibitors of Akt and mTOR [4, 11]. While these agents show clinical efficacy, their use is often limited by significant toxicities, most notably hyperglycemia, which results from the pathway's fundamental role in insulin signaling and glucose homeostasis [6, 13, 15].

Other names

PI3K-Akt survival signaling pathwayPI3K/Akt pathwayPI3K-Akt-mTOR pathwayPhosphoinositide 3-kinase-Protein kinase B pathwayPI3K-Akt survival pathway

Inhibition of the PI3K-Akt-mTOR signaling axis by targeting specific nodes (PI3K, Akt, or mTOR) to suppress oncogenic signaling, induce apoptosis, and inhibit cell proliferation and metabolism.