PIK3CA is the most frequently mutated oncogene in human cancer and PI3K and AKT inhibitors are a standard of care therapy in PIK3CA mutant breast cancer. However, in most patients, it is unknown which PI3K mutations are activating and/or drug-sensitizing. We have previously characterized double mutations in PI3K which hyperactivate PI3K resulting in increased PI3K and AKT inhibitor sensitivity (Vasan et al. Science 2019, Sivakumar…Sokol, Vasan Clin Cancer Res 2023). We now will comprehensively characterize PI3K protein variants using deep mutational scanning and structural biology. This work will define the repertoire of activating and drug-sensitive patient mutations and will guide the development of mutant-selective PI3K inhibitors.