Genomic profiling of biliary tract cancer cell lines reveals molecular subtypes and actionable drug targets
Journal Title
iScience
Publication Type
Journal Article
Abstract
Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although 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 harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. 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, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. 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.
Publisher
Elsevier
WEHI Research Division(s)
Personalised Oncology
PubMed ID
31731200
Open Access at Publisher's Site
https://doi.org/10.1016/j.isci.2019.10.044
NHMRC Grants
NHMRC/1126119
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-11-20 02:45:22
Last Modified: 2019-11-21 09:57:54
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