Integrated multiomic analysis of cholangiocarcinoma defines novel molecular subtypes associated with clinical outcome and identifies TNK1 as a therapeutic target

ABSTRACT: Despite remarkable advances in cancer genomics and targeted therapy, cholangiocarcinoma (CCA) is still one of the deadliest cancers. Current translational approaches have focused on genomic alterations, while leaving proteomic alterations, that may more directly pinpoint therapeutic targets, unexplored. To address these knowledge gaps, we performed multiomic characterization of all three CCA subtypes, using whole exome sequencing, mRNA sequencing, and proteome/phosphoproteome profiling. Integrative dimensional reduction approaches revealed RNA, protein and phosphoprotein features driving tumor heterogeneity. These features defined three molecular clusters associated with unique pathways: immunomodulatory (cluster 1), metabolic (cluster 2), and chromosomal stability/apoptosis (cluster 3). We observed that cluster assignment was not related to anatomic subtype but was associated with overall survival after curative-intent resection. Further, we utilized a hierarchical all-against-all approach, which identified multi-omic features and pathways associated with overall survival and lymph node metastases, clinically relevant endpoints for selecting patient treatments. Kinase enrichment analysis of molecular features identified non-receptor tyrosine protein kinase TNK1 as a highly active kinase for cluster 2. We developed a radial support vector machine model that mapped to multiomically-characterized patient derived xenograft (PDX) models resulting in the selection of PDX models for each cluster. Importantly, we confirmed that treating with a selective TNK1 inhibitor significantly reduced tumor growth in a cluster 2 PDX, but not a cluster 1 or 3 PDX. Overall, we concluded that integrated multiomic characterization provides translational insights by defining unique molecular subtypes, identifying molecular features associated with clinical outcomes, and uncovering novel therapeutic targets.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver, Bile Duct

DISEASE(S): Cholangiocarcinoma

SUBMITTER: Akhilesh Pandey  

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD059245 | Pride | 2026-06-29

REPOSITORIES: Pride