Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets
AuthorLau, DK; Mouradov, D; Wasenang, W; Luk, IY; Scott, CM; Williams, DS; Yeung, YH; Limpaiboon, T; Iatropoulos, GF; Jenkins, LJ; ...
University of Melbourne Author/sNikfarjam, Mehrdad; Sieber, Oliver; Mariadason, John; Mouradov, Dmitri; Tebbutt, Niall; Williams, David; Weickhardt, Andrew; Jenkins, Lauren
AffiliationSurgery (Austin & Northern Health)
Medical Biology (W.E.H.I.)
Medicine and Radiology
Document TypeJournal Article
CitationsLau, D. K., Mouradov, D., Wasenang, W., Luk, I. Y., Scott, C. M., Williams, D. S., Yeung, Y. H., Limpaiboon, T., Iatropoulos, G. F., Jenkins, L. J., Reehorst, C. M., Chionh, F., Nikfarjam, M., Croagh, D., Dhillon, A. S., Weickhardt, A. J., Muramatsu, T., Saito, Y., Tebbutt, N. C. ,... Mariadason, J. M. (2019). Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets. ISCIENCE, 21, pp.624-+. https://doi.org/10.1016/j.isci.2019.10.044.
Access StatusOpen Access
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.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References