The present invention relates to compositions, methods, and kits for treating cancers with HER2 targeting agents and preventing resistance thereto. In particular embodiments, non-HER2-amplified cancers are treated with HER2 targeting agents, wherein the cancer stem cells in the cancer express HER2 and/or HER2 indicator marker. The present invention also relates to compositions, methods, and kits for detecting expression of HER2 and/or a HER2 indicator marker in non-HER2-amplified cancer samples from a subject, and identifying the subject as responsive to treatment with a HER2 targeting agent and/or treating the subject with a HER2 targeting agent.
