These pharmacological vulnerabilities are supported by comparative synthetic lethality, gene expression, and correlative tissue studies in clinical specimens of CDH1 mutation carriers, which indicate select perturbations of GPCR, actin-related, ERK1–ERK2, or FAK and c-Src kinase activity as signaling alterations and possible targets selective for CDH1-mutant gastric cancer cells. The gene discussed is PTK2; the disease is gastric cancer.