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