Class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) (PI3K/mTOR)

Class I phosphoinositide 3-kinases (PI3K) and the mechanistic target of rapamycin (mTOR) are central components of the PI3K/AKT/mTOR signaling pathway, which serves as a master regulator of cellular growth, metabolism, and survival (Fruman et al., 2017). Class I PI3Ks are lipid kinases that respond to extracellular signals to produce PIP3, while mTOR is a serine/threonine kinase that integrates nutrient and energy status through two distinct complexes, mTORC1 and mTORC2 (Saxton & Sabatini, 2017). Dysregulation of this axis, often via PIK3CA mutations or PTEN loss, is one of the most frequent alterations in human cancers, promoting tumor progression and therapeutic resistance (Thorpe et al., 2015). Dual PI3K/mTOR inhibitors were developed to provide a more comprehensive blockade of the pathway than selective inhibitors, specifically to prevent the compensatory activation of AKT that occurs when only one node is inhibited (Massacesi et al., 2016). While these agents show significant preclinical potency, their clinical application is often limited by a narrow therapeutic window and systemic toxicities, including hyperglycemia and gastrointestinal distress (Janku et al., 2018).

Other names

PI3K/mTORPI3K/AKT/mTOR pathwayDual PI3K/mTOR targetPhosphatidylinositol 3-kinase and mechanistic target of rapamycin

Dual ATP-competitive inhibition of Class I PI3K isoforms (p110α, p110β, p110δ, p110γ) and the mTOR kinase (mTORC1 and mTORC2 complexes).