Phosphoinositide 3-kinase-AKT-mechanistic target of rapamycin (PI3K-AKT-mTOR) signaling pathway (PI3K-AKT-mTOR)

The Phosphoinositide 3-kinase-AKT-mechanistic target of rapamycin (PI3K-AKT-mTOR) signaling pathway is a fundamental intracellular network that coordinates cellular responses to growth factors, nutrients, and energy status [2, 4]. Activation begins with PI3K-mediated production of PIP3 at the plasma membrane, which recruits the serine/threonine kinase AKT (Protein Kinase B) for phosphorylation and activation [1, 2]. Once active, AKT regulates a vast array of downstream effectors, including the mTOR complexes, to promote protein synthesis, cell cycle progression, and glucose metabolism while suppressing pro-apoptotic signals [2, 5]. Dysregulation of this pathway is a hallmark of many human cancers, frequently occurring through activating mutations in PIK3CA or AKT1, or the loss of the inhibitory phosphatase PTEN [4, 5]. Consequently, the pathway is a major target for therapeutic development, with AKT-specific inhibitors like capivasertib recently gaining regulatory approval for certain breast cancers [3]. However, because the pathway is essential for normal insulin signaling and glucose homeostasis, therapeutic inhibition often leads to significant side effects such as hyperglycemia and gastrointestinal distress [3, 4].

Other names

AKT signaling pathwayProtein kinase B signaling pathwayPI3K-AKT-mTOR axisAKT-mTOR pathway

Drugs targeting this pathway primarily act through ATP-competitive inhibition of AKT isoforms, allosteric inhibition of AKT activation by binding to the pleckstrin homology (PH) domain, or inhibition of upstream (PI3K) and downstream (mTOR) nodes to disrupt the signaling cascade [2, 4].