Journal article

Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets

David K Lau, Dmitri Mouradov, Wiphawan Wasenang, Ian Y Luk, Cameron M Scott, David S Williams, Yvonne H Yeung, Temduang Limpaiboon, George F Iatropoulos, Laura J Jenkins, Camilla M Reehorst, Fiona Chionh, Mehrdad Nikfarjam, Daniel Croagh, Amardeep S Dhillon, Andrew J Weickhardt, Toshihide Muramatsu, Yoshimasa Saito, Niall C Tebbutt, Oliver M Sieber Show all

iScience | CELL PRESS | Published : 2019

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 m..

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Grants

Awarded by Victorian Cancer Agency


Awarded by NHMRC


Awarded by NHMRC Medical Postgraduate Scholarship


Funding Acknowledgements

This project was supported by the Victorian Cancer Agency (TRP13083), NHMRC Senior Research Fellowships to JMM (1046092) and OMS (1126119), and the Operational Infrastructure Support Program, Victorian Government, Australia. DL, LJ, and GI were supported by La Trobe University Australian Postgraduate Awards, and DL a scholarship from the Pancare Foundation, and GI a scholarship from the Hellenic Society of Medical Oncology. FC was supported by NHMRC Medical Postgraduate Scholarship (1017737), and YHY supported by a Fellowship from the ANZ Trustees Foundation (Brian Smith Endowment). We thank AGIOS Pharmaceuticals for measurement of 2-HG levels. The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.