Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets
| Autor: | Wiphawan Wasenang, Amardeep S. Dhillon, Yvonne Yeung, Temduang Limpaiboon, Dmitri Mouradov, Oliver M. Sieber, Daniel Croagh, Ian Y. Luk, Laura J. Jenkins, Niall C. Tebbutt, George F. Iatropoulos, Toshihide Muramatsu, Camilla M. Reehorst, Andrew Weickhardt, Cameron M. Scott, David K. Lau, Yoshimasa Saito, John M. Mariadason, Mehrdad Nikfarjam, David S. Williams, Fiona Chionh |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
IDH1 Genomics 02 engineering and technology Receptor tyrosine kinase Article Transcriptome 03 medical and health sciences Genetics lcsh:Science Exome Gene Cancer Multidisciplinary biology Mesenchymal stem cell Biological Sciences 021001 nanoscience & nanotechnology 3. Good health 030104 developmental biology biology.protein Cancer research lcsh:Q Human genome 0210 nano-technology |
| Zdroj: | iScience iScience, Vol 21, Iss, Pp 624-637 (2019) |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical Abstract Highlights • BTC cell lines harbor similar genomic alterations to primary tumors • Transcriptomic profiling of BTC cell lines identified two molecular subtypes • MAPK signaling is activated in BTC via multiple mechanisms • BTC lines with deregulated ERBB2 or FGFRs respond to specific targeted therapies Biological Sciences; Genetics; Genomics; Cancer |
| Databáze: | OpenAIRE |
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