Zhou Yimin, Tao Qiongyan, Luo Chubin, Chen Jinsong, Chen Genwen, Sun Jianyong
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Sci. 2025 Jun;116(6):1715-1729. doi: 10.1111/cas.70057. Epub 2025 Mar 18.
Primary or acquired mutations in RAS/RAF genes resulting in cetuximab resistance have limited its clinical application in colorectal cancer (CRC) patients. The mechanism of this resistance remains unclear. RNA sequencing from cetuximab-sensitive and -resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab-resistant CRC patients. In vitro, in vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab-resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti-tumor effect. Furthermore, in vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN-γ pathway in cetuximab-resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN-γ then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8 T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti-tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab-resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.
RAS/RAF基因的原发性或获得性突变导致西妥昔单抗耐药，限制了其在结直肠癌（CRC）患者中的临床应用。这种耐药机制尚不清楚。对西妥昔单抗敏感和耐药标本进行的RNA测序显示，在西妥昔单抗耐药的CRC患者中，色氨酸途径激活，IDO1和IDO2升高。体外、体内及临床标本证实，西妥昔单抗治疗后IDO1和IDO2以及犬尿氨酸/色氨酸（Kyn/Trp）上调。此外，IDO抑制剂依帕司他可有效抑制西妥昔单抗耐药CRC细胞的迁移和增殖，同时促进细胞凋亡。与依帕司他单药治疗相比，西妥昔单抗与依帕司他联合使用显示出更强的协同抗肿瘤作用。此外，体内实验证实联合治疗可有效抑制肿瘤生长。机制上，KEGG通路分析显示西妥昔单抗耐药CRC组织中IFN-γ通路激活。荧光素酶报告基因检测证实西妥昔单抗治疗后IDO1的转录活性。沉默IFN-γ可抑制西妥昔单抗诱导的上调。此外，我们观察到联合治疗降低了色氨酸代谢产物犬尿氨酸的浓度，促进了CD8 T淋巴细胞浸润，并增强了肿瘤微环境中M1巨噬细胞的极化，从而发挥强大的抗肿瘤免疫作用。总体而言，我们的结果证实了西妥昔单抗与依帕司他联合治疗西妥昔单抗耐药CRC具有显著的治疗效果。我们的发现可能为克服CRC中对西妥昔单抗的耐药性提供一个新靶点。
