Introduction: The Challenge of Heterogeneity in HER2-Positive Gastric Cancer
Human epidermal growth factor receptor 2 (HER2; ERBB2) serves as a critical driver and therapeutic target in approximately 15% to 20% of gastric cancers (GC). While the introduction of HER2-targeted agents, such as the monoclonal antibody trastuzumab and the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd), has significantly improved survival outcomes, the clinical benefit is often curtailed by the emergence of acquired resistance. A primary hurdle in managing HER2-positive GC is its profound interpatient and intrapatient heterogeneity. Unlike breast cancer, where HER2 expression is often uniform, gastric cancer frequently exhibits mosaic-like patterns of expression, complicating both diagnosis and treatment monitoring.
To address this complexity, a landmark study recently published in Gut (Sheng et al., 2026) utilized spatial transcriptomics to move beyond traditional bulk sequencing. By examining patient-matched samples before and after therapy, the researchers have provided a high-resolution map of how these tumors evade molecular blockade, offering a glimpse into the next generation of precision oncology.
Study Design: A Spatially Resolved Deep Dive
The study employed the GeoMx Digital Spatial Profiler (DSP) to analyze over 1,500 regions of interest (ROIs) across 30 gastric cancers. Crucially, the cohort included 15 patients with HER2-positive GC who were treated with trastuzumab followed by T-DXd upon progression. This patient-matched design allowed researchers to track the molecular evolution of individual tumors under the selective pressure of targeted therapy.
To ensure the robustness of their findings, the investigators validated their spatial transcriptomic data using immunohistochemistry (IHC), independent patient cohorts, and advanced functional models, including patient-derived xenografts (PDX) and organoids. This multi-layered approach bridged the gap between descriptive observation and mechanistic validation.
Unraveling Trastuzumab Resistance: Three Distinct Phenotypes
The analysis of trastuzumab-resistant samples revealed that tumors do not follow a single path to resistance. Instead, they appear to adopt one of several distinct molecular strategies:
1. The EMT and Immune-Evasive Axis
Approximately one-third of the patients progressed via an epithelial-mesenchymal transition (EMT) program. This structural transformation was closely associated with the upregulation of PD-L1 and the chemokine CCL2. This finding suggests that for a significant subset of patients, trastuzumab resistance is not merely a loss of HER2 signaling but a fundamental shift toward a mesenchymal, immune-suppressive state that may be susceptible to immune checkpoint inhibitors.
2. The ERAD Pathway and GOLM1
Another third of the resistant tumors exhibited activation of the endoplasmic reticulum-associated degradation (ERAD) pathway. A key marker in this group was GOLM1 (Golgi membrane protein 1). The ERAD pathway is typically involved in the quality control of protein folding; its upregulation in this context likely reflects a cellular adaptation to the stress induced by HER2 inhibition, providing a potential metabolic target for future therapies.
3. CLDN18.2 Upregulation: A Strategic Opportunity
Perhaps the most clinically actionable finding was the observed increase in Claudin 18.2 (CLDN18.2) expression in trastuzumab-resistant tumors. CLDN18.2 is a tight junction protein that has recently emerged as a major therapeutic target in gastric cancer. The fact that its expression increases after HER2-targeted therapy failure suggests a clear rationale for sequential therapy: targeting CLDN18.2 in the second- or third-line setting once HER2-directed options are exhausted.
T-DXd Resistance: Metabolic Shifts and Immune Escape
Trastuzumab deruxtecan (T-DXd) has revolutionized the treatment of HER2-positive GC, yet resistance remains inevitable. The spatial profiling of T-DXd-resistant tumors revealed mechanisms distinct from those of trastuzumab:
HLA Loss and Immune Evasion
In several cases, T-DXd resistance was characterized by the loss of human leukocyte antigen (HLA) molecules. Since the efficacy of ADCs like T-DXd may partially rely on an intact immune microenvironment to clear damaged tumor cells, the loss of HLA represents a sophisticated method of escaping both the drug and the host’s immune surveillance.
Metabolic Reprogramming
Resistant tumors also showed a marked increase in oxidative phosphorylation (OXPHOS) pathways. This metabolic shift suggests that cells surviving the cytotoxic payload of T-DXd (deruxtecan, a topoisomerase I inhibitor) do so by optimizing their energy production, potentially opening the door for OXPHOS inhibitors as sensitizing agents.
Clinical Implications and Expert Commentary
This study underscores that HER2-positive gastric cancer is a moving target. The transition from HER2-dominance to EMT-driven or metabolic-driven states necessitates a dynamic approach to treatment.
Experts in the field note that the discovery of PD-L1 upregulation in EMT-type resistance provides a biological rationale for combining HER2-targeted agents with anti-PD-1/PD-L1 therapies, a strategy already being explored in trials like KEYNOTE-811. Furthermore, the identification of CLDN18.2 as a ‘back-up’ target after trastuzumab failure could lead to standardized protocols for re-biopsying patients at the time of progression to guide the choice of subsequent ADC or monoclonal antibody therapy.
However, the study also highlights the limitations of current diagnostic techniques. Standard bulk biopsies may miss the spatial ‘pockets’ of resistance identified by GeoMx. As spatial profiling technologies become more accessible, they may eventually become a standard part of the diagnostic workup for refractory gastrointestinal cancers.
Conclusion: A Blueprint for Future Trials
Sheng et al. have provided a comprehensive atlas of resistance in HER2-positive GC. By delineating the roles of EMT, ERAD, CLDN18.2, and metabolic reprogramming, this research provides the evidence base needed to design more effective combination and sequential therapy trials. The ultimate goal is to transform gastric cancer from a disease of frequent recurrence into one where targeted blocks are applied precisely, anticipating and neutralizing the tumor’s escape mechanisms before they manifest clinically.
References
1. Sheng T, Sundar R, Srivastava S, et al. Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy. Gut. 2026;75(4):733-747. PMID: 41167802.
2. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric cancer. Nature. 2021;600:727–730.
3. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab plus EOX in patients with advanced CLDN18.2-positive gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2021;32(5):607-619.
