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The purpose of this project is to use patient-derived xenograft (PDX) models and genetically-engineered mouse models (GEMMs) of HER2+ breast cancer brain metastases (BCBM) to test novel CDK4/6-based combination therapies for activity against HER2+ BCBM. By using anti-CDK4/6 drugs with other targeted therapies we will be able test the potential synergy of drug combinations against HER2+ BCBM. Due to pending approval of involving human subjects, we do not have any activities to report on using patient derived xenograft (PDX) models. However, we have made a considerable progress in mouse tumor cells and syngeneic mouse models of BCBM. Our positive preliminary results from mouse models laid the foundation for further developing effective therapeutic strategies against specific subtypes of breast cancer brain metastases, which is important for deliver pre-clinical information to guide the rational design of promising clinical trials.