Zhang Saiqun, Chen Yuling, Li Chang, Zhao Jian, Jiao Min, Zhang Mengzhu, Ma Chenkang, Wang Anqi, Li Jianjun, Zeng Yuanyuan, Zhu Jianjie, Mu Chuanyong, Huang Jian-An, Liu Zeyi
Department of Pulmonary and Critical Care Medicine, The First Affiliat ed Hospital of Soochow University, Suzhou, 215006, China.
Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
J Transl Med. 2025 Jul 25;23(1):831. doi: 10.1186/s12967-025-06874-9.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have exhibited remarkable efficacy against EGFR-mutated lung cancer. However, the majority of patients receiving EGFR-TKIs face a grim prognosis due to acquired drug resistance. Melanoma cell adhesion molecule (MCAM), a highly glycosylated type I transmembrane protein belonging to the immunoglobulin superfamily, is upregulated in EGFR-TKI-resistant EGFR-mutant lung adenocarcinoma. The objective of this study was to investigate the role and mechanism of MCAM in mediating resistance to EGFR-TKIs.
qRT-PCR, Western blot, and immunofluorescence techniques were employed to analyze the expression of MCAM in EGFR-TKI sensitive and resistant cells.CCK-8 assay and subcutaneous xenograft model in nude mice were utilized to investigate the correlation between MCAM expression level and resistance to EGFR-TKIs. Furthermore, receptor tyrosine kinase (RTK) phosphorylation antibody array, co-immunoprecipitation, immunofluorescence, and dual-luciferase assay were employed to elucidate its molecular mechanism.
The expression level of MCAM was significantly higher in EGFR-TKI resistant lung adenocarcinoma cells compared to EGFR-TKI sensitive lung adenocarcinoma cells. CCK-8 cytotoxicity assay demonstrated that overexpression of MCAM enhanced resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma cells. Overexpression of MCAM promoted the growth of transplanted tumors in nude mice, while having a limited effect on the efficacy of EGFR-TKIs. Moreover, interaction between MCAM and integrin β1 activated the downstream JAK3 signaling pathway, thereby promoting resistance to EGFR-TKIs. The transcription factor STAT2 activates transcription of the target gene MCAM by binding to its promoter region.
MCAM can enhance the resistance of EGFR-mutant lung adenocarcinoma cells to EGFR-TKIs, both in vitro and in vivo. Through its interaction with integrin β1, MCAM activates JAK3 protein, thereby stimulating cell proliferation and contributing to the development of acquired resistance in sensitive cell lines. The expression of MCAM is regulated by the transcription factor STAT2. This study presents a novel therapeutic strategy for patients with EGFR-TKI resistance.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）已显示出对EGFR突变型肺癌具有显著疗效。然而，由于获得性耐药，大多数接受EGFR-TKIs治疗的患者预后严峻。黑色素瘤细胞粘附分子（MCAM）是一种高度糖基化的I型跨膜蛋白，属于免疫球蛋白超家族，在EGFR-TKI耐药的EGFR突变型肺腺癌中上调。本研究的目的是探讨MCAM在介导对EGFR-TKIs耐药中的作用及机制。
采用qRT-PCR、蛋白质免疫印迹法和免疫荧光技术分析MCAM在EGFR-TKI敏感和耐药细胞中的表达。利用CCK-8法和裸鼠皮下异种移植模型研究MCAM表达水平与对EGFR-TKIs耐药性之间的相关性。此外，采用受体酪氨酸激酶（RTK）磷酸化抗体芯片、免疫共沉淀法、免疫荧光法和双荧光素酶测定法阐明其分子机制。
与EGFR-TKI敏感的肺腺癌细胞相比，MCAM在EGFR-TKI耐药的肺腺癌细胞中的表达水平显著更高。CCK-8细胞毒性试验表明，MCAM的过表达增强了EGFR突变型肺腺癌细胞对EGFR-TKIs的耐药性。MCAM的过表达促进了裸鼠移植瘤的生长，而对EGFR-TKIs的疗效影响有限。此外，MCAM与整合素β1之间的相互作用激活了下游JAK3信号通路，从而促进了对EGFR-TKIs的耐药性。转录因子STAT2通过与其启动子区域结合来激活靶基因MCAM的转录。
MCAM在体外和体内均可增强EGFR突变型肺腺癌细胞对EGFR-TKIs的耐药性。通过与整合素β1相互作用，MCAM激活JAK3蛋白，从而刺激细胞增殖并导致敏感细胞系中获得性耐药的发生。MCAM的表达受转录因子STAT2的调控。本研究为EGFR-TKI耐药患者提供了一种新的治疗策略。
