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
Affiliations
David K. Lau
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
Dmitri Mouradov
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
Wiphawan Wasenang
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
Ian Y. Luk
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
Cameron M. Scott
Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
David S. Williams
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
Yvonne H. Yeung
Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
Temduang Limpaiboon
Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
George F. Iatropoulos
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
Laura J. Jenkins
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
Camilla M. Reehorst
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
Fiona Chionh
Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
Mehrdad Nikfarjam
Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia
Daniel Croagh
Department of Surgery, Monash Medical Centre, Monash University, Melbourne, VIC 3168, Australia
Amardeep S. Dhillon
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
Andrew J. Weickhardt
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
Toshihide Muramatsu
Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
Yoshimasa Saito
Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
Niall C. Tebbutt
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
Oliver M. Sieber
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
John M. Mariadason
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; Corresponding author
Summary: 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. : Biological Sciences; Genetics; Genomics; Cancer Subject Areas: Biological Sciences, Genetics, Genomics, Cancer
