HER2-targeted therapy resistance in breast cancer: Molecular mechanisms, therapeutic evolution, and precision oncology approaches

Globally, breast cancer (BC) ranks among the most common cancers and is the foremost cause of cancer-related death in women. Human Epidermal Growth Factor Receptor (HER2)-targeted medicines have significantly improved the clinical results of HER2-positive breast cancer, a physiologically aggressive subtype. Monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), and antibody drug conjugates (ADCs) have significantly enhanced survival outcomes across early and metastatic disease. However, intrinsic and acquired resistance remain inevitable in a substantial proportion of patients, limiting long-term therapeutic responses. Resistance to HER2-directed therapies arises through diverse and often overlapping mechanisms, including receptor structural alterations, activation of compensatory signaling pathways, immune evasion, downstream pathway reactivation, and tumor heterogeneity. In addition, emerging evidence highlights HER2-low expression as a therapy induced and adaptive resistance phenotype under therapeutic pressure. In parallel, resistance to next -generation ADCs involves additional mechanisms, including antigen heterogeneity, impaired intracellular processing and payload specific adaptations. This review provides a comprehensive and integrative overview of the molecular basis of HER2-targeted therapy resistance and discusses its clinical implications, with a focus on improving therapeutic strategies in HER2-positive and HER2-low BC.