{
  "abstract": "Background CLDN18.2 has emerged as a promising therapeutic target in gastric and gastro-oesophageal junction cancers. However, its clinical efficacy in pancreatic ductal adenocarcinoma (PDAC) has been modest, suggesting the presence of regulatory mechanisms impairing its efficacy.Objective We aim to investigate how O-linked N-acetylglucosaminylation (O-GlcNAcylation) affects CLDN18.2 subcellular localisation, tumour progression and therapeutic resistance in PDAC, while exploring strategies to restore treatment sensitivity.Design This study used samples from patients with PDAC, along with the following models: humanised patient-derived xenograft (PDX), patient-derived organoids (PDOs), orthotopic PDO xenograft, KPC mice (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre) and KPC-Cldn18.2 knockout (KO) mice.Results KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation and hyperglycaemia cooperatively drive CLDN18.2 O-GlcNAcylation at T204, promoting CLDN18.2 cytoplasmic accumulation. O-GlcNAcylated CLDN18.2 promotes pancreatic cancer migration, invasion and metastases and reduces its sensitivity to anti-CLDN18.2 based targeted therapy. Mechanistically, O-GlcNAcylated CLDN18.2 exhibits reduced binding to PTP1B, leading to enhanced tyrosine phosphorylation. O-GlcNAcylated CLDN18.2 recruits Src via SH2 domain, triggering Src activation. Genetic (T204A) or pharmacological blockade of O-GlcNAcylation restores CLDN18.2 membrane localisation and suppresses tumour progression. Therapeutically, low-dose MRTX1133 (KRASG12D inhibitor) reduces O-GlcNAcylation and synergises with CLDN18.2-targeted therapy in KRAS mutant PDAC models with minimal side effects.Conclusions KRAS mutations and hyperglycaemia drive O-GlcNAcylation of CLDN18.2 at its C-terminal T204 site. O-GlcNAcylated CLDN18.2 promotes poor prognosis and reduces the effectiveness of CLDN18.2-targeted therapies. Low dose MRTX1133 restores CLDN18.2 membrane localisation by reducing its O-GlcNAcylation and augments CLDN18.2-targeted therapy efficacy, offering a novel combinatorial strategy for KRAS-mutant PDAC.",
  "authors": [
    {
      "affiliations": [
        "Department of Breast Surgery, Fudan University Shanghai Cancer Center；Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China",
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Jing Liu"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Xupeng Hou"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Lin Li"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, China"
      ],
      "name": "Weiwei Bai"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Tianxing Zhou"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Moran Chen"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Hu Yu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry Chinese Academy of Sciences, Beijing, China"
      ],
      "name": "Hongxia Sun"
    },
    {
      "affiliations": [
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Administrative Office of National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Tingting Xu"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Yifei Wang"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Antao Chang"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Yukuan Feng"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Jun Yu"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Chongbiao Huang"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Yongjie Xie"
    },
    {
      "affiliations": [
        "Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China",
        "State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China",
        "Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China"
      ],
      "name": "Jihui Hao"
    }
  ],
  "title": "KRAS mutation-driven O-GlcNAcylation of CLDN18.2 enhances the progression of pancreatic cancer and reduces the efficacy of CLDN18.2-targeted therapy",
  "uid": "c049dc0c-dec1-548d-8e50-2ec3d8ae7d3f"
}