Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) E542K mutant (PI3Kα E542K)

PI3Kα E542K is a recurrent somatic hotspot mutation located in the helical domain (Exon 9) of the p110α catalytic subunit of Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3Kα), encoded by the PIK3CA gene (OncoKB, 2024; MDPI, 2023). This mutation involves a glutamic acid to lysine substitution at residue 542, which disrupts the inhibitory contact between the p110α helical domain and the nSH2 domain of the p85 regulatory subunit, leading to constitutive, growth factor-independent kinase activity (PatSnap, 2024; NIH, 2022). The resulting hyperactivation of the PI3K/AKT/mTOR signaling pathway promotes key hallmarks of cancer, including enhanced cell proliferation, survival, and metabolic reprogramming such as increased glycolysis (NIH, 2018; e-century, 2021). It is a major driver in several solid tumors, particularly hormone receptor-positive (HR+) breast cancer, where it is also associated with resistance to endocrine therapies like fulvestrant (OncoKB, 2024; PatSnap, 2023). Clinical management involves the use of PI3Kα-selective inhibitors like alpelisib, while newer allosteric and mutant-selective inhibitors like RLY-2608 and inavolisib are being developed to improve the therapeutic window by sparing wild-type PI3Kα and reducing systemic side effects such as hyperglycemia (AACR, 2022; ResearchGate, 2025).

Other names

PIK3CA E542Kp110α E542KPhosphoinositide-3-kinase catalytic subunit alpha E542KPI3-kinase subunit alpha E542KPIK3CA helical domain mutation E542K

Selective inhibition of the PI3K alpha isoform, allosteric inhibition of mutant PI3K alpha, and targeted degradation of the mutant p110 alpha protein, leading to the suppression of the PI3K/AKT/mTOR signaling pathway (PatSnap, 2024; AACR, 2022; ResearchGate, 2025).