Abstract
Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naïve tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (ALDH1A1 inhibitor) exhibited synergism with nab-paclitaxel in the organoid model for stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in stem-like and metabolism subtypes. Poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis reproduced not only the three subtypes but also showed heterogeneity in iCC. This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.
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