Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) E545K (PI3Kα E545K)

PI3Kα E545K is a specific oncogenic mutation in the PIK3CA gene, which encodes the p110α catalytic subunit of the Class IA phosphoinositide 3-kinase (PI3K) enzyme (UniProt P42336). This mutation is located in the helical domain (Exon 9) and results in the substitution of glutamic acid with lysine, which disrupts the inhibitory contact between the p110α subunit and the nSH2 domain of the p85 regulatory subunit (Zhao & Vogt, 2008). This disruption leads to constitutive, growth factor-independent activation of the PI3K/AKT/mTOR signaling pathway, driving uncontrolled cell growth and survival (Samuels et al., 2004). It is one of the most frequent hotspot mutations found in human cancers, particularly in breast, colorectal, and endometrial malignancies. Therapeutic targeting of this mutant protein is primarily achieved through alpha-selective PI3K inhibitors like alpelisib and inavolisib, which are designed to block the hyperactive kinase activity (André et al., 2019). However, clinical use is often limited by systemic side effects such as hyperglycemia and hyperinsulinemia, as PI3Kα is a critical mediator of the insulin signaling pathway in normal tissues (Hopkins et al., 2018). Monitoring for PIK3CA mutations in tissue or liquid biopsies is essential for identifying patients likely to benefit from these targeted therapies.

Other names

PIK3CA E545Kp110α E545KPhosphoinositide-3-kinase catalytic subunit alpha E545Kp110-alpha E545KPIK3CA helical domain mutation

Selective or pan-class I phosphoinositide 3-kinase (PI3K) inhibition, specifically targeting the ATP-binding site of the p110α catalytic subunit to prevent the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3).