PIK3CA

About PIK3CA

PIK3CA on chromosome 3q26.32 encodes p110 alpha, the catalytic subunit of class I phosphatidylinositol 3 kinase, which generates the lipid messenger PIP3 to activate AKT and mTOR signaling, promoting cell growth, survival, and metabolism. PIK3CA is one of the most frequently mutated oncogenes in human cancer. Activating mutations are particularly common in hormone receptor positive, HER2 negative breast cancer, and also occur often in endometrial, colorectal, cervical, bladder, and head and neck cancers. Hotspot mutations such as E545K in the helical domain and H1047R in the kinase domain constitutively activate the enzyme. PTEN loss often coexists with PIK3CA mutation, both activating the same pathway. Alpelisib, an alpha selective PI3K inhibitor, was approved for PIK3CA mutated advanced breast cancer in combination with fulvestrant, and inavolisib and the AKT inhibitor capivasertib have since been approved for related settings. Mosaic activating PIK3CA mutations arising during embryonic development cause the PIK3CA related overgrowth spectrum, including CLOVES syndrome, Klippel Trenaunay syndrome, megalencephaly capillary malformation syndrome, and macrodactyly, conditions in which alpelisib has also been used. PIK3CA thus illustrates how the same mutation can cause cancer or a developmental disorder depending on when and where it arises.