Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) E542K (PIK3CA E542K)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) E542K is a specific oncogenic mutant form of the p110α protein, the catalytic component of Class IA PI3K. This mutation involves a glutamic acid to lysine substitution at position 542 within the helical domain, which leads to constitutive, growth-factor-independent activation of the PI3K/AKT/mTOR signaling pathway [1][2]. By disrupting the inhibitory contact between the p110α helical domain and the nSH2 domain of the p85 regulatory subunit, the E542K mutation enhances the enzyme's recruitment to the plasma membrane and its catalytic efficiency [3]. It is recognized as a major hotspot mutation frequently identified in various malignancies, particularly hormone receptor-positive breast cancer, where it drives tumor growth and contributes to endocrine therapy resistance [4]. Targeted therapies like alpelisib have been specifically developed and approved to inhibit this mutant kinase, although their clinical use is often limited by systemic metabolic side effects, such as hyperglycemia, due to the critical role of PI3K alpha in insulin signaling [5][6]. Identification of this specific mutation via genomic profiling is essential for patient selection in precision oncology protocols [4].

Other names

p110-alpha E542KPI3K-alpha E542KPhosphoinositide-3-kinase catalytic alpha polypeptide E542KPI3K catalytic subunit alpha E542K

Selective ATP-competitive inhibition of the p110-alpha catalytic subunit of PI3K, which prevents the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby blocking the activation of the downstream AKT/mTOR signaling pathway.