EGFR TKIs通过PI3K/AKT/SP1/C1GALT1途径抑制MUC1糖基化，从而增强EGFR突变型NSCLC中TnMUC1 CAR-T的疗效。

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-06-17 DOI:10.1016/j.xcrm.2025.102199

Ziwei Zhou, Si Chen, Jianli Zhao, Xin Du, Haibin Yin, Chao Zhou, Hai Hu, Yunfang Yu, Yinghua Zhu, Herui Yao

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引用次数: 0

摘要

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）是EGFR突变型癌症（非小细胞肺癌[NSCLC]）的标准一线治疗药物，其客观缓解率（ORR）约为60%-70%。然而，优化它们的治疗效果仍然是一个挑战。NSCLC细胞表达肿瘤特异性的低糖基化汤姆森-努维勒（Tn）粘蛋白1 （MUC1）抗原，使其成为TnMUC1嵌合抗原受体(CAR)-T细胞治疗的合适靶点。本研究表明，EGFR TKIs在体外和体内均可增强TnMUC1 CAR-T细胞治疗EGFR突变型NSCLC的疗效。EGFR TKIs通过降低MUC1糖基化而上调TnMUC1，从而改善TnMUC1 CAR-T细胞的识别和细胞毒性。具体来说，EGFR TKIs调节tnmuc1相关的糖基转移酶，其中core1-beta1,3-半乳糖基转移酶1 （C1GALT1）被鉴定为EGFR TKIs下调的关键酶，表明C1GALT1是一个潜在的治疗靶点。

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EGFR TKIs suppress MUC1 glycosylation through the PI3K/AKT/SP1/C1GALT1 pathway to enhance TnMUC1 CAR-T efficacy in EGFR-mutant NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for EGFR-mutant cancer (non-small cell lung cancer [NSCLC]), achieving an objective response rate (ORR) of approximately 60%-70%. However, optimizing their therapeutic efficacy remains a challenge. NSCLC cells express the tumor-specific hypoglycosylated Thomsen-nouvelle (Tn) mucin 1 (MUC1) antigen, making them suitable targets for TnMUC1 chimeric antigen receptor (CAR)-T cell therapy. This study shows that EGFR TKIs enhance the efficacy of TnMUC1 CAR-T cell therapy in EGFR-mutant NSCLC, both in vitro and in vivo. EGFR TKIs upregulate TnMUC1 by reducing MUC1 glycosylation, thereby improving TnMUC1 CAR-T cell recognition and cytotoxicity. Specifically, EGFR TKIs modulate TnMUC1-related glycosyltransferases, with core1-beta1,3-galactosyltransferase 1 (C1GALT1) identified as a key enzyme downregulated by EGFR TKIs, suggesting C1GALT1 as a potential therapeutic target.

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.