Spatial Profiling of HER2-Positive Gastric Cancer Reveals Resistance Mechanisms

06 Mar 20264 min read0 viewsJournal Feed

GIST

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.

Clinical Editorial

Strategic focus: study design and scope

The analysis linked interpatient and intrapatient heterogeneity to mechanisms of resistance to HER2-directed therapy.

Validation relied on immunohistochemistry, independent cohorts, and patient-derived xenografts and organoid models.

Spatial profiling approach: The study employed GeoMx Digital Spatial Profiler to map gene expression across more than 1500 regions of interest in 30 gastric cancers, with 15 of these harboring HER2 amplification treated with trastuzumab and/or trastuzumab deruxtecan (T-DXd).

Contextual findings: HER2+ tumor microenvironment and resistance signals

Tumor immune context: HER2+ tumors showed PD-L1 expression within the spatial tumor microenvironment.
Additional target landscape: Increased expression of CLDN18.2 was observed in trastuzumab-resistant tumors, highlighting a potentially actionable target in this subset.
EMT association: Approximately one-third of trastuzumab-resistant HER2+ gastric cancers exhibited epithelial-mesenchymal transition, with concurrent upregulation of PD-L1 and CCL2.

Divergent resistance pathways by therapy

Trastuzumab resistance mechanisms: About one-third of cases developed EMT, linked to PD-L1 and CCL2 upregulation; another portion displayed activation of the ER-assisted degradation pathway, with genes such as GOLM1 implicated.
T-DXd resistance signals: In tumors resistant to T-DXd, there were observed shifts including loss of HLA expression and enrichment of oxidative phosphorylation pathways, indicating a distinct resistance axis from trastuzumab.

Evidence synthesis and validation

Cross-model corroboration: Findings were supported by independent patient cohorts and functional models, including xenografts and organoids derived from patients.