Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting IDO ‐Mediated Tryptophan Metabolism

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.