Trastuzumab Resistance in HER2-Positive Gastric Cancer: From Molecular Mechanisms to Precision Therapeutics

Trastuzumab remains the only targeted agent that has received approval as an initial therapy for HER2-amplified gastric cancer. When used alongside platinum-fluoropyrimidine chemotherapy, it has been shown to prolong overall survival compared with chemotherapy alone. However, the long-term clinical benefit is restricted because most patients develop acquired resistance within one year of starting therapy. Multiple tumor-intrinsic mechanisms (activation of alternative receptor tyrosine kinases, downstream signaling, altered glycosylation, YAP/mTOR reactivation, noncoding RNAs) and microenvironmental factors (metabolic crosstalk, macrophage polarization, extracellular vesicle transfer) have been implicated. Metabolic reprogramming, especially enhanced glycolysis, the mevalonate pathway, and glutamine metabolism, has emerged as a central mechanism that not only contributes to intrinsic trastuzumab resistance but also modulates the tumor immune microenvironment, thereby influencing therapeutic response. Spatial metabolomics (MALDI-IMS), integrated genomic/transcriptomic analyses, and functional studies have begun to identify biomarkers and drugable vulnerabilities. Promising strategies to overcome resistance include combined targeting of glutamine metabolism, angiogenesis, and macrophage polarization; dual blockade of ErbB2 with novel antibodies (H2-18) plus trastuzumab; PAM pathway inhibitors (DIACC3010) combined with trastuzumab; antibody-drug conjugates (trastuzumab deruxtecan); and immune checkpoint combinations (e.g., pembrolizumab or camrelizumab with trastuzumab-based regimens). This review integrates recent preclinical and clinical evidence on factors contributing to resistance to trastuzumab in HER2-amplified GC and highlights translational opportunities for biomarker-driven combination therapies.