PIK3CA encodes the catalytic subunit alpha of phosphoinositide 3-kinase (PI3K), a lipid kinase that phosphorylates phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 recruits and activates AKT1 and other PH domain-containing proteins, triggering signaling cascades that regulate cell growth, survival, proliferation, motility, and morphology downstream of receptor tyrosine kinases including those for EGF, insulin, and VEGF. Beyond lipid kinase activity, PIK3CA exhibits serine-protein kinase activity toward regulatory and target proteins. The gene is essential for vascular development, cardiomyogenesis, and vasculogenesis in embryonic contexts. PIK3CA is the most frequently altered oncogene in multiple human malignancies. Somatic mutations—predominantly E542K and E545K (exon 9) or H1047R (exon 20)—occur in approximately 25–40% of breast cancers 1, 39% of penile cancers 2, and are frequent in head and neck squamous cell carcinoma, colorectal cancer, angiosarcoma, and other solid tumors. Gene amplification also drives oncogenic hyperactivation 3. These alterations promote tumorigenesis through PI3K/AKT/mTOR pathway dysregulation 4. PIK3CA-related overgrowth syndrome (PROS) encompasses somatic mosaic gain-of-function mutations causing a spectrum including CLOVES, MCAP, and Klippel-Trenaunay syndrome, characterized by vascular malformations and asymmetric overgrowth 5, 6. PI3K inhibitors—including alpelisib, copanlisib, buparlisib, and inavolisib—are approved or in clinical development. Alpelisib combined with endocrine therapy improves outcomes in hormone receptor-positive, HER2-negative breast cancers, particularly those with PIK3CA mutations 7. Recent evidence suggests that neddylation pathway genes are synthetic lethal dependencies in PIK3CA-mutated head and neck cancers, potentially offering new therapeutic avenues 8.