Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy
Taotao Sheng, Raghav Sundar, Supriya Srivastava, Xuewen Ong, Su Ting Tay, Haoran Ma, Tomoyuki Uchihara, Benedict Shi Xiang Lian, Takeshi Hagihara, Mei Kong, Chang Xu, Shamaine Wei Ting Ho, Kie Kyon Huang, Angie Lay Keng Tan, Michelle Ng, Jiamin Toh, Clara Shi Ya Ng, Vincenzo Nasca, Chiara Pircher, Giovanni Randon, Silvia Giordano, Simona Corso, Jeffrey Huey Yew Lum, Ming Teh, Joseph J. Zhao, Jimmy Bok Yan So, Giovanna Sabella, Shyam Prabhakar, Jeeyun Lee, Wei Peng Yong, Matthew Chau Hsien Ng, Kohei Shitara, Jessica Gasparello, Matteo Fassan, Filippo Pietrantonio, Patrick Tan
Abstract
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.