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A CMTM6 Nanobody Overcomes EGFR-TKI Resistance in Non-Small Cell Lung Cancer

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机构: [1]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China. [2]Musculoskeletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People's Hospital, Beijing, 100044, China. [3]Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, NHC Key Laboratory of Medical Immunology, Peking University Center for Human Disease Genomics, Beijing, 100191, China. [4]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China. [5]Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, 100191, China. [6]Thoracic Oncology Ward, West China Hospital Cancer Center, Sichuan University, Chengdu, 610041, China. [7]The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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关键词: CMTM6 EGFR EGFR-TKIs resistance NSCLC nanobody

摘要:
Aberrant EGFR signaling drives non-small cell lung cancer (NSCLC) development, and despite the success of tyrosine kinase inhibitor (TKI) therapies in treating NSCLC, TKI resistance remains a major obstacle. Here, we report that the chemokine-like transmembrane protein CMTM6 is physically associated with EGFR. CMTM6 is shown to be co-localized with EGFR in recycling endosomes that are marked by RAB11, thereby preventing EGFR from lysosome-mediated degradation in NSCLC cells. The level of CMTM6 is elevated in NSCLC, and high expression of CMTM6 is associated with enhanced colocalization of CMTM6 with EGFR and RAB11 in NSCLC tumors and correlated with a poor prognosis in NSCLC patients. A CMTM6-targeting nanobody is developed and administration of this agent leads to blocking of the CMTM6-EGFR interaction, reduction of the EGFR protein level, and inhibition of the proliferation of TKI-resistant NSCLC cells in vitro and suppression of the growth of EGFR-TKI-resistant NSCLC in both cell line-derived xenografts and patient-derived xenograft models. The study indicates that CMTM6 is a stabilizer of EGFR in endocytic trafficking and provides evidence to support targeting CMTM6 as a potential therapeutic strategy to overcome TKI resistance in NSCLC treatment.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

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出版当年[2025]版:
大类 | 1 区 综合性期刊
小类 | 1 区 化学:综合 1 区 材料科学:综合 1 区 纳米科技
最新[2025]版:
大类 | 1 区 综合性期刊
小类 | 1 区 化学:综合 1 区 材料科学:综合 1 区 纳米科技
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第一作者机构: [1]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China.
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通讯作者:
通讯机构: [1]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China. [4]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China. [5]Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, 100191, China.
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