Wang Chunyan, Xiong Mengting, Zhu Yifei, Li Kun, Ni Jian
Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
Department of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
Eur J Med Res. 2025 Jul 21;30(1):642. doi: 10.1186/s40001-025-02894-9.
Tyrosine kinase inhibitors (TKIs) are a class of therapies used to target specific genetic mutations such as epidermal growth factor receptor (EGFR) mutations in cancer treatment. This study investigates the function of epithelial membrane protein 3 (EMP3) in EGFR-TKI resistance in lung adenocarcinoma (LUAD). Human LUAD cells HCC827 and H1975 were exposed to different doses of osimertinib or erlotinib to generate TKI-resistant cell lines. These cells exhibited increased expression of EMP3. EMP3 overexpression in parental cells significantly increased TKI resistance, as well as promoted proliferation, migration, and stem cell characteristics. Epithelial-mesenchymal transition (EMT) is a major cause for EMP3 upregulation, as overexpression of ZEB1 increased EMP3 expression. By contrast, inhibition of the TGF/β signaling with LY2109761 reduced EMP3 expression in cells. In vivo, EMP3-overexpressing mouse 3LL cells exhibited strengthened tumorigenic activity in C57BL/6 mice in the presence of osimertinib treatment, accompanied by increased stem cell markers. Notably, the LY2109761 treatment reduced TKI resistance and diminished expansion, migration, and stemness in cancer cells induced by EMP3 overexpression. In conclusion, this study indicates that EMP3, upregulated upon EMT, contributes to EGFR-TKI resistance in LUAD cells.
酪氨酸激酶抑制剂（TKIs）是一类用于靶向特定基因突变的疗法，例如在癌症治疗中靶向表皮生长因子受体（EGFR）突变。本研究调查了上皮膜蛋白3（EMP3）在肺腺癌（LUAD）对EGFR-TKI耐药中的作用。将人LUAD细胞HCC827和H1975暴露于不同剂量的奥希替尼或厄洛替尼，以产生TKI耐药细胞系。这些细胞中EMP3的表达增加。亲代细胞中EMP3的过表达显著增加了TKI耐药性，并促进了增殖、迁移和干细胞特性。上皮-间质转化（EMT）是EMP3上调的主要原因，因为ZEB1的过表达增加了EMP3的表达。相比之下，用LY2109761抑制TGF/β信号可降低细胞中EMP3的表达。在体内，在奥希替尼治疗存在的情况下，过表达EMP3的小鼠3LL细胞在C57BL/6小鼠中表现出增强的致瘤活性，同时干细胞标志物增加。值得注意的是，LY2109761治疗降低了TKI耐药性，并减少了由EMP3过表达诱导的癌细胞的增殖、迁移和干性。总之，本研究表明，EMT时上调的EMP3促成了LUAD细胞对EGFR-TKI的耐药。
