Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha E545K (PIK3CA E545K)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) E545K is a specific oncogenic mutant form of the p110α catalytic subunit of Class IA PI3K (UniProt: P42336). The E545K mutation, located in the helical domain (exon 9), involves a substitution of glutamic acid with lysine, which disrupts the inhibitory contact with the nSH2 domain of the p85 regulatory subunit (PubMed: 17606925). This disruption leads to constitutive, growth factor-independent activation of the PI3K/AKT/mTOR signaling pathway, promoting oncogenic transformation, cell survival, and proliferation (PubMed: 18332432). PIK3CA E545K is one of the most frequent hotspot mutations found in human cancers, particularly in breast, colorectal, and endometrial malignancies (PubMed: 25544370). Therapeutic targeting of this mutant protein is achieved through alpha-selective PI3K inhibitors like alpelisib, which are designed to block the ATP-binding pocket of the catalytic subunit (FDA: Piqray Label). Clinical challenges include managing off-target metabolic effects, most notably hyperglycemia, as PI3Kα plays a central role in systemic insulin signaling (PubMed: 30022161).

Other names

p110alpha E545KPI3K-alpha E545KPhosphoinositide-3-kinase catalytic alpha polypeptide E545KPI3KCA E545K mutation

ATP-competitive inhibition of the PI3K alpha catalytic subunit, which prevents the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby suppressing the AKT/mTOR signaling pathway (PubMed: 30401665).