Genomic profiling of biliary tract cancer cell lines reveals molecular subtypes and actionable drug targets.

Summary Biliary tract cancers (BTCs) currently have no approved targeted therapies. While genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbour similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumours. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumours. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, while surprisingly, IDH1-mutant lines did not respond to IDH1-inhibitors. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers.