{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore"
      ],
      "name": "Taotao Sheng"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore",
        "Yong Loo Lin School of Medicine, National University of Singapore, Singapore",
        "Department of Haematology-Oncology, National University Cancer Institute, Singapore",
        "Singapore Gastric Cancer Consortium, Singapore",
        "Department of Medicine (Medical Oncology), Yale University, New Haven, Connecticut, USA"
      ],
      "name": "Raghav Sundar"
    },
    {
      "affiliations": [
        "Department of Medicine, National University Hospital, Singapore"
      ],
      "name": "Supriya Srivastava"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Xuewen Ong"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Su Ting Tay"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Haoran Ma"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Tomoyuki Uchihara"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Benedict Shi Xiang Lian"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Takeshi Hagihara"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore"
      ],
      "name": "Mei Suen Kong"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Chang Xu"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore"
      ],
      "name": "Shamaine Wei Ting Ho"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Kie Kyon Huang"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Angie Lay Keng Tan"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore"
      ],
      "name": "Michelle Shu Wen NG"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore"
      ],
      "name": "Jiamin Toh"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Clara Shi Ya Ng"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Vincenzo Nasca"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Chiara Carlotta Pircher"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Giovanni Randon"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Torino, Candiolo, Italy",
        "Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy"
      ],
      "name": "Silvia Giordano"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Torino, Candiolo, Italy",
        "Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy"
      ],
      "name": "Simona Corso"
    },
    {
      "affiliations": [
        "Department of Pathology, National University Hospital, Singapore"
      ],
      "name": "Jeffrey Huey Yew Lum"
    },
    {
      "affiliations": [
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore",
        "Yong Loo Lin School of Medicine, National University of Singapore, Singapore",
        "Department of Haematology-Oncology, National University Cancer Institute, Singapore",
        "Department of Medicine, National University Hospital, Singapore"
      ],
      "name": "Joseph J Zhao"
    },
    {
      "affiliations": [
        "Department of Pathology, National University Hospital, Singapore"
      ],
      "name": "Ming Teh"
    },
    {
      "affiliations": [
        "Yong Loo Lin School of Medicine, National University of Singapore, Singapore",
        "Singapore Gastric Cancer Consortium, Singapore",
        "Department of Surgery, National University of Singapore, Singapore",
        "Department of Surgery, University Surgical Cluster, National University Health System, Singapore",
        "NUS Centre for Cancer Research, National University of Singapore, Singapore"
      ],
      "name": "Jimmy Bok Yan So"
    },
    {
      "affiliations": [
        "Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Giovanna Sabella"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore",
        "Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore",
        "Cancer Science Institute of Singapore, National University of Singapore, Singapore"
      ],
      "name": "Shyam Prabhakar"
    },
    {
      "affiliations": [
        "Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea",
        "Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Korea"
      ],
      "name": "Jeeyun Lee"
    },
    {
      "affiliations": [
        "Division of Medical Oncology, National Cancer Centre, Singapore"
      ],
      "name": "Matthew Chau Hsien Ng"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, National Cancer Center Hospital East, Kashiwa, Japan"
      ],
      "name": "Kohei Shitara"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Padua, Padua, Italy"
      ],
      "name": "Jessica Gasparello"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Padua, Padua, Italy",
        "Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy"
      ],
      "name": "Matteo Fassan"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Filippo Pietrantonio"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore",
        "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore",
        "Singapore Gastric Cancer Consortium, Singapore",
        "Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore",
        "Singhealth/Duke-NUS Institute of Precision Medicine, National Heart Centre, Singapore"
      ],
      "name": "Patrick Tan"
    }
  ],
  "title": "Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy",
  "uid": "06331068-a4b0-5f1e-b611-74731d19207b"
}