We analyzed how cancer cells with a broken PTEN gene respond differently to genetic disruptions and drugs across many cancer types. The key finding is that when PTEN is lost, cancer cells switch their dependence from one form of the PI3K enzyme (p110α) to another (p110β), creating a specific vulnerability. Drugs targeting AKT (like afuresertib) are especially effective against PTEN-lost cancers of the uterus and ovary. About 180,000 US cancer patients per year have PTEN-lost tumors, and many cancer types with this alteration — including melanoma and bladder cancer — currently lack targeted clinical trials.