机构：[1]Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China研究所北京市神经外科研究所首都医科大学附属天坛医院[2]Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China[3]Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China[4]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China重点科室诊疗科室神经外科神经外科首都医科大学附属天坛医院[5]Department of Radio-therapy, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China首都医科大学附属天坛医院[6]Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, 100050 Beijing, China[7]Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, 100875 Beijing, China[8]Center of Brain Tumor, Beijing Institute for Brain Disorders, 100069 Beijing, China[9]China National Clinical Research Center for Neurological Diseases, 100050 Beijing, China[10]Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea[11]Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea[12]Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China[13]Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China
Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in similar to 14% of cases with significantly worse prognosis Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in pre-clinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.
基金：
National Key Research and Development Plan [2016YFC0902500]; Natural Science Foundation of China (NSFC)/Research Grants Council (RGC), Hong Kong, China Joint Research Scheme [81761168038, N_HKUST606/17]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81502495, 81502606, 81702460]; Capital Foundation of Medical Developments [2016-1-1072]; Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support [ZYLX201708]; Beijing Nova ProgramBeijing Municipal Science & Technology Commission [Z171100001117022]; Beijing Administration of Hospitals' Youth Program [QML20160502]; Collaborative Research Fund (CRF), Hong Kong [C6002-17GF]; Hong Kong Epigenomics Project [LKCCFL18SC01-E]; Korea Health Technology R&D project through KHIDI - Ministry of Health & Welfare, Republic of Korea [HI14C3418]; BDBI Lab
第一作者机构：[1]Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China
共同第一作者：
通讯作者：
通讯机构：[1]Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China[2]Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China[3]Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China[4]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China[7]Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, 100875 Beijing, China[8]Center of Brain Tumor, Beijing Institute for Brain Disorders, 100069 Beijing, China[9]China National Clinical Research Center for Neurological Diseases, 100050 Beijing, China[12]Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China
推荐引用方式(GB/T 7714)：
Hu Huimin,Mu Quanhua,Bao Zhaoshi,et al.Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor[J].CELL.2018,175(6):1665-+.doi:10.1016/j.cell.2018.09.038.
APA：
Hu, Huimin,Mu, Quanhua,Bao, Zhaoshi,Chen, Yiyun,Liu, Yanwei...&Jiang, Tao.(2018).Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.CELL,175,(6)
MLA：
Hu, Huimin,et al."Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor".CELL 175..6(2018):1665-+
生物