Wang Yuepeng
Department of Medical Oncology, Xinglongtai District, Panjin Central Hospital, No.32, Liaohe Middle RoadLiaoning Province 124010, Panjin City, China.
Appl Biochem Biotechnol. 2025 Mar;197(3):1773-1789. doi: 10.1007/s12010-024-05112-0. Epub 2024 Nov 28.
Cholangiocarcinoma is a hepatobiliary system tumor with a high mortality rate. Although durvalumab and trastuzumab deruxtecan (T-DXd) have shown efficacy in treating cancers such as non-small cell lung cancer, their effects and regulatory mechanisms in cholangiocarcinoma remain unclear. In this study, we aimed to investigate the role and mechanism of durvalumab and T-DXd in inducing apoptosis in cholangiocarcinoma cells. Cholangiocarcinoma cells were treated with varying concentrations of durvalumab and T-DXd, either individually or in combination, to evaluate their effects. Apoptosis was quantified using flow cytometry. Quantitative real-time PCR (qPCR) and Western blotting were used to measure the mRNA expression and protein levels of genes associated with apoptosis and cell cycle regulation. The underlying mechanism was further explored through pathway enrichment analysis of differentially expressed genes (DEGs) and corroborated by qPCR and Western blotting. Xenotransplantation models using immune-deficient NOD-SCID/IL2Rγnull (NSG) mice were established to assess the in vivo effects of durvalumab and T-DXd. Our results showed that both durvalumab and T-DXd inhibited cholangiocarcinoma cell proliferation in a dose-dependent manner. Both agents promoted apoptosis and arrested the cell cycle of cholangiocarcinoma cells, with the combination treatment having the most significant effect. Furthermore, treatment with durvalumab, T-DXd, and the combination downregulated the protein levels of early growth response 1 (EGR1) by inactivating the p38 mitogen-activated protein kinase (MAPK) pathway. In vivo experiments indicated that durvalumab and T-DXd prolonged the survival of NSG mice bearing cholangiocarcinoma xenografts. In conclusion, our findings demonstrated that durvalumab and T-DXd synergistically promoted apoptosis in cholangiocarcinoma cells by inhibiting EGR1 expression through inactivation of the p38 MAPK pathway. This study confirmed the potential of durvalumab and T-DXd for the treatment of cholangiocarcinoma.
胆管癌是一种死亡率很高的肝胆系统肿瘤。尽管度伐利尤单抗和曲妥珠单抗德鲁昔单抗（T-DXd）在治疗非小细胞肺癌等癌症方面已显示出疗效，但其在胆管癌中的作用和调控机制仍不清楚。在本研究中，我们旨在探讨度伐利尤单抗和T-DXd在诱导胆管癌细胞凋亡中的作用及机制。用不同浓度的度伐利尤单抗和T-DXd单独或联合处理胆管癌细胞，以评估其效果。使用流式细胞术对细胞凋亡进行定量分析。采用定量实时PCR（qPCR）和蛋白质印迹法检测与细胞凋亡和细胞周期调控相关基因的mRNA表达和蛋白质水平。通过对差异表达基因（DEG）进行通路富集分析进一步探索潜在机制，并通过qPCR和蛋白质印迹法进行验证。建立了使用免疫缺陷的NOD-SCID/IL2Rγnull（NSG）小鼠的异种移植模型，以评估度伐利尤单抗和T-DXd的体内效果。我们的结果表明，度伐利尤单抗和T-DXd均以剂量依赖的方式抑制胆管癌细胞增殖。两种药物均促进胆管癌细胞凋亡并使细胞周期停滞，联合治疗效果最为显著。此外，度伐利尤单抗、T-DXd及联合治疗通过使p38丝裂原活化蛋白激酶（MAPK）通路失活，下调早期生长反应1（EGR1）的蛋白质水平。体内实验表明，度伐利尤单抗和T-DXd延长了携带胆管癌异种移植物的NSG小鼠的生存期。总之，我们的研究结果表明，度伐利尤单抗和T-DXd通过使p38 MAPK通路失活抑制EGR1表达，协同促进胆管癌细胞凋亡。本研究证实了度伐利尤单抗和T-DXd治疗胆管癌的潜力。
