Metabolic hallmarks of trastuzumab resistance

The HER2-targeted monoclonal antibody trastuzumab has significantly improved the survival of patients with HER2-positive breast cancer (HER2+ BC) in both early and metastatic disease. Therapeutic resistance remains an inevitable challenge in the advanced setting, ultimately limiting the long-term efficacy of trastuzumab. Numerous mechanisms of trastuzumab resistance and response heterogeneity have been described, most involving alterations in HER2 receptor levels and reactivation of HER2 downstream signaling. However, the growing number of metabolic escape routes that allow HER2+ BC cells to evade HER2 inhibition have received little attention.

We comprehensively review the metabolic strategies that HER2+ BC cells adopt to enable trastuzumab resistance, grouping them into a structured classification that takes into account their functional nature, namely: (1) metabolic reprogramming - how cells maintain an adequate supply of energy and biosynthetic precursors to survive, grow and proliferate despite HER2 inhibition; (2) adaptive stress response - how cells increase their resilience to survive trastuzumab-induced stress and damage; and (3) metabolic-signaling crosstalk - how key survival pathways redirect metabolism to reinforce trastuzumab resistance feedback loops.

The metabolic hallmarks of trastuzumab resistance may help to identify high-quality predictive biomarkers and to rationally develop optimized therapeutic strategies to counteract trastuzumab resistance metabolically.