Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges

SIMPLE SUMMARY: Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) represents a subgroup of breast cancer characterized by an aggressive behaviour and a particular sensitiveness to HER2-targeted agents. Because of the frequent occurrence of acquired resistance to anti-HER2 therapy, novel agents were investigated, including antibody-drug conjugates (ADCs). ADCs represent an emerging class of anticancer agents consisting of a humanized monoclonal antibody bounded to a cytotoxic drug by a molecular linker. HER2-positive mBC represents the first solid tumor in which ADCs, like Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), demonstrated to improve clinical outcomes compared to prior standards of care. Nonetheless, despite their effectiveness, resistance to T-DM1 and T-DXd still occurs in most of the patients treated with these ADCs, warranting an improved understanding of the mechanisms underlying resistance. This review aims to describe the emerging mechanisms of resistance to ADCs targeting HER2, highlighting the potential strategies to overcome resistance and further improve clinical outcomes of patients with metastatic breast cancer. ABSTRACT: The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the decrease of HER2 expression, the alteration of intracellular trafficking, the impairment of lysosome functions, the drug expulsion through efflux pumps and the activation of alternative signal pathways. Instead, the decrease of HER2 expression and SLX4 loss of function mutations represent the first evidences of mechanisms of resistance to T-DXd, according to the results of DAISY trial. Several strategies are under evaluation to overcome resistances to anti-HER2 ADCs and improve clinical outcomes in patients progressing on these agents: combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors and synthetic DNA-damaging agents are emerging as promising approaches. Furthermore, novel anti-HER2 ADCs with innovative structures and mechanisms of action are in development, in the attempt to further improve the activity and tolerability of currently available agents.