Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/22129
Title: Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets.
Austin Authors: Lau, David K ;Mouradov, Dmitri;Wasenang, Wiphawan;Luk, Ian Y;Scott, Cameron M;Williams, David S ;Yeung, Yvonne H ;Limpaiboon, Temduang;Iatropoulos, George F ;Jenkins, Laura J;Reehorst, Camilla M;Chionh, Fiona;Nikfarjam, Mehrdad ;Croagh, Daniel;Dhillon, Amardeep S;Weickhardt, Andrew J ;Muramatsu, Toshihide;Saito, Yoshimasa;Tebbutt, Niall C ;Sieber, Oliver M;Mariadason, John M
Affiliation: Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
Austin Health, Heidelberg, Victoria, Australia
Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia
Department of Surgery, Monash Medical Centre, Monash University, Melbourne, VIC 3168, Australia
Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
Department of Biochemistry & Molecular Biology, Monash University, Melbourne, VIC 3800, Australia
Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia
Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
School of Medicine, Deakin University, Geelong, VIC 3216, Australia
School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
Issue Date: 22-Nov-2019
metadata.dc.date: 2019-10-31
Publication information: iScience 2019; 21: 624-637
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/22129
DOI: 10.1016/j.isci.2019.10.044
ORCID: 0000-0001-9123-7684
PubMed URL: 31731200
Type: Journal Article
Subjects: Biological Sciences
Cancer
Genetics
Genomics
Appears in Collections:Journal articles

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