Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy
Menée à l'aide d'organoïdes, de xénogreffes et d'une analyse transcriptomique de plus de 1 500 régions de 30 tumeurs gastriques dont 15 HER2+ traitées par trastuzumab et T-DXd (trastuzumab déruxtécan), cette étude identifie des mécanismes de résistance à la thérapie ciblée
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 , résumé, 2025