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; John M Mariadason

doi:10.1016/j.isci.2019.10.044

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

iScience. 2019 Nov 22:21:624-637. doi: 10.1016/j.isci.2019.10.044. Epub 2019 Oct 31.

Authors

David K Lau¹, Dmitri Mouradov², Wiphawan Wasenang³, Ian Y Luk¹, Cameron M Scott⁴, David S Williams¹, Yvonne H Yeung⁴, Temduang Limpaiboon⁵, George F Iatropoulos¹, Laura J Jenkins¹, Camilla M Reehorst¹, Fiona Chionh⁴, Mehrdad Nikfarjam⁶, Daniel Croagh⁷, Amardeep S Dhillon⁸, Andrew J Weickhardt¹, Toshihide Muramatsu⁹, Yoshimasa Saito⁹, Niall C Tebbutt¹, Oliver M Sieber¹⁰, John M Mariadason¹¹

Affiliations

¹ Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia.
² Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
³ 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.
⁴ Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia.
⁵ Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand.
⁶ Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia.
⁷ Department of Surgery, Monash Medical Centre, Monash University, Melbourne, VIC 3168, Australia.
⁸ Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Medicine, Deakin University, Geelong, VIC 3216, Australia.
⁹ Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan.
¹⁰ Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia; Department of Biochemistry & Molecular Biology, Monash University, Melbourne, VIC 3800, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia.
¹¹ Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: john.mariadason@onjcri.org.au.

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.

Keywords: Biological Sciences; Cancer; Genetics; Genomics.