Phosphoinositide 3-kinase and phosphoinositide 3-kinase-related kinase family (PI3K/PIKK)

The Phosphoinositide 3-kinase (PI3K) and Phosphoinositide 3-kinase-related kinase (PIKK) families comprise a group of structurally related enzymes that play fundamental roles in cellular signaling, growth, and genome stability [1, 12]. PI3Ks are primarily lipid kinases that convert phosphatidylinositol-4,5-bisphosphate (PIP2) into the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), thereby activating the AKT/mTOR pathway to promote cell survival and metabolism [16, 23]. The PIKK family includes atypical protein kinases such as mTOR, which regulates protein synthesis in response to nutrients, and ATM, ATR, and DNA-PKcs, which are essential for sensing and repairing DNA damage [5, 13]. Dysregulation of these kinases, often through PIK3CA mutations or PTEN loss, is a frequent driver of oncogenesis and resistance to therapy in various cancers [3, 18]. Consequently, numerous inhibitors have been developed, ranging from isoform-specific PI3K inhibitors like alpelisib to dual PI3K/mTOR inhibitors and DNA damage response (DDR) inhibitors [1, 9]. While these agents show significant therapeutic potential, their clinical use is often limited by on-target toxicities such as hyperglycemia, gastrointestinal issues, and immunosuppression [2, 11]. Effective patient selection often relies on molecular biomarkers, such as PIK3CA mutation status, to identify those most likely to benefit from targeted therapy [3, 14].

Other names

PI3K/PIKK familyPhosphatidylinositol 3-kinase familyPI3K-related protein kinase familyPI3K/AKT/mTOR pathway kinases

Inhibition of the catalytic activity of PI3K and PIKK family members, typically through ATP-competitive binding, which prevents the phosphorylation of lipid or protein substrates and disrupts downstream signaling pathways involved in cell growth, survival, and DNA repair.