HER2-targeted therapies such as trastuzumab effectively control systemic disease but resistance to treatment is common and up to 50% of patients progress to incurable brain metastases. Tyrosine kinase inhibitors (TKIs) are increasingly used as second line therapy but the best clinical setting for these inhibitors and whether they have a place in the clinic for the treatment of breast cancer brain metastasis remains unclear. Progress on that front has been hindered by the lack of clinically relevant models of HER2 breast cancer brain metastasis.
Aim: To develop and characterise a robust mouse model of spontaneous HER2 breast cancer brain metastasis for evaluation of TKI efficacy.
Methods: We selected and characterised clonal variants from a mammary tumour that developed spontaneously in an immune-competent Balb/c mouse. The efficacy of a panel of TKIs was tested in vitro and neratinib was selected for further evaluation in vivo. Resistant variants were developed by long-term exposure to neratinib.
Results: We identified a clonal variant (TBCP-1) that naturally expresses high levels of HER2 and aggressively metastasises from the mammary gland to the brain in immune-competent mice. Evaluation of TKIs against human and mouse tumour lines in vitro identified neratinib as the most potent TKI. Neratinib’s superior efficacy was associated with its unique ability to induce cell death by ferroptosis, a mechanism distinct from apoptosis. Neratinib as a first line neoadjuvant therapy potently inhibited tumour growth and spontaneous metastasis to brain and other organs. Neratinib-resistant TBCP-1 variants acquired a mesenchymal phenotype, showed altered expression of integrin receptors and cross-resistance to other TKIs but could be resensitised by treatment with integrin inhibitors.
Conclusions: TBCP-1 is the only model that aggressively recapitulates the spontaneous spread of HER2 breast cancer to the brain in immune-competent mice. Further evaluation of neoadjuvant neratinib alone or in combination with integrin inhibitors is warranted.