Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, China.
Oncogene. 2023 Nov;42(47):3503-3513. doi: 10.1038/s41388-023-02856-7. Epub 2023 Oct 16.
In non-small cell lung cancer (NSCLC), the overexpression or abnormal activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and drug resistance. EGFR tyrosine kinase inhibitors (TKIs) are currently the first-line treatment of NSCLC. However, patients inevitably acquired EGFR TKIs resistance mutations, which led to disease progression, so it is urgent to find new treatment. Here, we report that D-mannose up-regulates lysosomal activity by enhancing TFE3-mediated lysosomal biogenesis, thereby increasing the degradation of EGFR and significantly down-regulating its protein level. Therefore, D-mannose significantly inhibited the proliferation, migration and invasion of wild-type EGFR (WT-EGFR) and EGFR mutant cells (E746-A750 deletion, L858R and T790M mutations) in vitro. Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.
在非小细胞肺癌（NSCLC）中，表皮生长因子受体（EGFR）的过表达或异常激活与肿瘤进展和耐药性有关。EGFR 酪氨酸激酶抑制剂（TKI）是目前 NSCLC 的一线治疗药物。然而，患者不可避免地会产生 EGFR TKI 耐药突变，导致疾病进展，因此迫切需要寻找新的治疗方法。在这里，我们报告 D-甘露糖通过增强 TFE3 介导的溶酶体生物发生来上调溶酶体活性，从而增加 EGFR 的降解，并显著下调其蛋白水平。因此，D-甘露糖在体外显著抑制野生型 EGFR（WT-EGFR）和 EGFR 突变细胞（E746-A750 缺失、L858R 和 T790M 突变）的增殖、迁移和侵袭。D-甘露糖的口服给药在小鼠中强烈抑制肿瘤生长，与奥希替尼具有相似的效果。综上所述，这些数据表明 D-甘露糖可能代表 NSCLC 临床治疗的一种新策略。
