Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy
Menée à l'aide d'organoïdes, de xénogreffes dérivées de tumeurs de patients, de données de cohortes et de l'analyse transcriptomique spatiale ou immunochimique d'échantillons tumoraux, cette étude met en évidence l'acquisition de mécanismes de résistance au trastuzumab ou au trastuzumab déruxtécan dans les cellules gastriques cancéreuses HER2+
Background : Human epidermal growth factor receptor 2 (HER2; ERBB2) is overexpressed or amplified in 15–20% of gastric cancers (HER2+ GC). Within individual HER2+ GCs, HER2/ERBB2 expression is often variable. Although HER2 therapeutic targeting improves outcomes for HER2+ GC patients, acquired resistance is frequent.
Objective : To spatially interrogate HER2+ GC interpatient and intrapatient heterogeneity and resistance mechanisms associated with HER2-targeting agents (trastuzumab, trastuzumab deruxtecan (T-DXd)).
Design : Spatial transcriptomic analysis (GeoMx Digital Spatial Profiler) was applied to >1500 regions of interest in 30 GCs—these contained 15 HER2+ GCs treated with trastuzumab and T-DXd subsequently. Analysis of patient-matched samples with acquired trastuzumab or T-DXd resistance revealed escape mechanisms. Results were validated by immunohistochemistry, independent cohorts and patient-derived xenografts and organoids.
Results : HER2+ tumours exhibited PD-L1 expression within the spatial tumour microenvironment. We observed increased expression of CLDN18.2, a promising therapeutic target, in trastuzumab-resistant tumours. One-third of HER2+ GC patients developed epithelial-mesenchymal transition (EMT) on trastuzumab resistance, associated with PD-L1 and CCL2 upregulation. Another third of trastuzumab-resistant HER2+ GC patients activated the endoplasmic reticulum-associated degradation (ERAD) pathway including genes such as GOLM1. HLA loss and increases in oxidative phosphorylation pathways were observed in T-DXd-resistant GCs.
Conclusion : Our results delineate multiple acquired resistance mechanisms to trastuzumab and T-DXd in HER2+ GC in vivo. This information may guide trials combining trastuzumab or T-DXd with new agents to enhance the efficacy and durability of HER2 blockade.
Gut , article en libre accès, 2026