Human epidermal growth factor receptor-2 (HER2)-targeted therapies such as Trastuzumab prolong survival in HER2+ve breast cancer patients. However, benefits stem primarily from improved control of extracranial disease and up to 50% of patients progress to incurable brain metastases due to acquired resistance and/or limited permeability across the blood-brain barrier. While small molecule tyrosine kinase inhibitors (TKIs) provide attractive alternatives to Trastuzumab, evaluation of their efficacy under various clinical scenarios has been limited by the lack of clinically relevant models of HER2+ve breast cancer that recapitulate spontaneous spread to the brain.
Here, we describe the development and characterisation of the only immune-competent mouse model of spontaneous HER2+ve brain metastatic breast cancer available worldwide (TBCP-1). Comparison of the efficacy of a panel of TKIs against mouse and human HER2+ve breast cancer lines identified the irreversible pan-TKI, neratinib, as the most potent inhibitor. Mechanistic studies and transcriptomics analyses indicate that the superior efficacy of neratinib is associated with its unique ability to induce death by ferroptosis. Importantly, we evaluated the efficacy of Neratinib under different clinical settings, and demonstrate for the first time that neoadjuvant neratinib inhibits primary tumour growth and metastasis to brain and other organs more potently than late intervention and significantly prolongs disease free survival.
Hence, our study introduces a new syngeneic pre-clinical model that faithfully mimics the spontaneous spread of HER2+ve breast cancer to the brain and provides the rationale for clinical evaluation of neoadjuvant neratinib in patients. We propose that ferroptosis could be exploited as a novel therapeutic strategy to enhance the efficacy of HER2-targeted therapies against brain metastasis.