Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets.
Biological Sciences
Cancer
Genetics
Genomics
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
22 Nov 2019
22 Nov 2019
Historique:
received:
05
07
2019
revised:
21
09
2019
accepted:
22
10
2019
pubmed:
16
11
2019
medline:
16
11
2019
entrez:
16
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31731200
pii: S2589-0042(19)30424-9
doi: 10.1016/j.isci.2019.10.044
pmc: PMC6889747
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
624-637Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Hepatology. 2014 Apr;59(4):1427-34
pubmed: 24122810
J Hepatol. 2017 Feb;66(2):424-441
pubmed: 27686679
Cancer Discov. 2016 Jul;6(7):727-39
pubmed: 27231123
World J Gastroenterol. 2005 May 14;11(18):2748-53
pubmed: 15884115
Cancer Cell. 2010 Mar 16;17(3):225-34
pubmed: 20171147
Mol Cell. 2005 Jan 21;17(2):215-24
pubmed: 15664191
Nat Genet. 2012 May 06;44(6):690-3
pubmed: 22561520
Oncologist. 2014 Mar;19(3):235-42
pubmed: 24563076
Science. 2013 May 3;340(6132):626-30
pubmed: 23558169
Oncotarget. 2016 Sep 6;7(36):58007-58021
pubmed: 27517322
Cell Cycle. 2014;13(20):3176-82
pubmed: 25485496
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
In Vitro Cell Dev Biol. 1989 Jun;25(6):503-10
pubmed: 2544546
Nat Genet. 2015 Sep;47(9):1003-10
pubmed: 26258846
Nat Genet. 2013 Dec;45(12):1474-8
pubmed: 24185513
Mol Cancer. 2011 Aug 26;10:102
pubmed: 21871105
Int J Oncol. 1997 Jun;10(6):1251-5
pubmed: 21533512
Oncologist. 2012;17(1):72-9
pubmed: 22180306
Nature. 2012 Aug 30;488(7413):665-9
pubmed: 22895187
Oncogene. 2018 Apr;37(15):1949-1960
pubmed: 29367755
J Hepatobiliary Pancreat Sci. 2012 Jul;19(4):342-53
pubmed: 22678429
J Clin Oncol. 2018 Jan 20;36(3):276-282
pubmed: 29182496
Res Exp Med (Berl). 1988;188(5):367-75
pubmed: 2852388
Genesis. 2007 Dec;45(12):762-7
pubmed: 18064675
Cancer Res. 2013 Feb 15;73(4):1298-307
pubmed: 23393200
Cell Death Discov. 2017 Nov 27;3:17069
pubmed: 29188076
Cell Rep. 2017 Jun 27;19(13):2878-2880
pubmed: 28658632
Cancer Discov. 2017 Oct;7(10):1116-1135
pubmed: 28667006
Cancer Discov. 2018 May;8(5):648-661
pubmed: 29483135
Hum Cell. 1988 Mar;1(1):95-7
pubmed: 3154020
Curr Gastroenterol Rep. 2011 Apr;13(2):182-7
pubmed: 21271364
Oncogene. 2013 Jun 20;32(25):3091-100
pubmed: 22824796
Nat Genet. 2014 Aug;46(8):872-6
pubmed: 24997986
Chin Clin Oncol. 2016 Oct;5(5):61
pubmed: 27829275
Nat Med. 2018 Aug;24(8):1192-1203
pubmed: 29988124
Br J Cancer. 2002 Jul 15;87(2):187-93
pubmed: 12107841
Nature. 2018 Feb 8;554(7691):189-194
pubmed: 29420467
Gan. 1980 Aug;71(4):574-5
pubmed: 7429092
Nat Rev Cancer. 2010 Feb;10(2):116-29
pubmed: 20094046
Gastroenterol Jpn. 1987 Aug;22(4):474-9
pubmed: 2889643
Clin Cancer Res. 2016 Jan 1;22(1):259-67
pubmed: 26373574
Cell Rep. 2019 Apr 23;27(4):1265-1276.e4
pubmed: 31018139
N Engl J Med. 2010 Apr 8;362(14):1273-81
pubmed: 20375404
Int J Oncol. 2019 Feb;54(2):753-763
pubmed: 30483760
Nature. 2017 Aug 10;548(7666):234-238
pubmed: 28783719
J Hepatol. 1985;1(6):579-96
pubmed: 4056357