Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner.
Active Transport, Cell Nucleus
Animals
Antineoplastic Agents, Alkylating
/ pharmacology
Cell Line, Tumor
Chromatin
/ genetics
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice
Oncogene Proteins, Fusion
/ antagonists & inhibitors
Protein Binding
Proto-Oncogene Protein c-fli-1
/ antagonists & inhibitors
RNA-Binding Protein EWS
/ antagonists & inhibitors
Sarcoma, Ewing
/ drug therapy
Trabectedin
/ pharmacology
Transcription Factors
/ genetics
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
26
10
2018
revised:
24
12
2018
accepted:
23
01
2019
pubmed:
7
2
2019
medline:
7
7
2020
entrez:
7
2
2019
Statut:
ppublish
Résumé
The successful clinical translation of compounds that target specific oncogenic transcription factors will require an understanding of the mechanism of target suppression to optimize the dose and schedule of administration. We have previously shown trabectedin reverses the gene signature of the EWS-FLI1 transcription factor. In this report, we establish the mechanism of suppression and use it to justify the reevaluation of this drug in the clinic in patients with Ewing sarcoma. Trabectedin evicts the SWI/SNF chromatin-remodeling complex from chromatin and redistributes EWS-FLI1 in the nucleus leading to a marked increase in H3K27me3 and H3K9me3 at EWS-FLI1 target genes. These effects only occur at high concentrations of trabectedin leading to suppression of EWS-FLI1 target genes and a loss of cell viability. These data provide the justification to evaluate trabectedin in the clinic on a short infusion schedule in combination with low-dose irinotecan with
Identifiants
pubmed: 30723142
pii: 1078-0432.CCR-18-3511
doi: 10.1158/1078-0432.CCR-18-3511
pmc: PMC6594545
mid: NIHMS1520011
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
Chromatin
0
EWS-FLI fusion protein
0
Oncogene Proteins, Fusion
0
Proto-Oncogene Protein c-fli-1
0
RNA-Binding Protein EWS
0
Transcription Factors
0
Trabectedin
ID0YZQ2TCP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3417-3429Subventions
Organisme : NCI NIH HHS
ID : R01 CA188314
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA236300
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA231641
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183776
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124736
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
Références
Cancer Res. 2016 Nov 15;76(22):6657-6668
pubmed: 27697767
Clin Cancer Res. 2008 Oct 15;14(20):6449-55
pubmed: 18927284
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13062-7
pubmed: 17656556
Mol Cancer Res. 2006 Nov;4(11):851-9
pubmed: 17114343
Expert Opin Ther Targets. 2005 Aug;9(4):825-30
pubmed: 16083345
Clin Cancer Res. 2014 Mar 1;20(5):1190-203
pubmed: 24277455
Cancer Chemother Pharmacol. 2016 Apr;77(4):663-71
pubmed: 26666647
Cancer Res. 2008 Apr 1;68(7):2176-85
pubmed: 18381423
EMBO J. 2005 Feb 23;24(4):800-12
pubmed: 15678104
Cell. 2017 Feb 9;168(4):629-643
pubmed: 28187285
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W187-91
pubmed: 24799436
Cell Cycle. 2008 Oct;7(20):3127-32
pubmed: 18927503
Clin Cancer Res. 2002 Dec;8(12):3893-903
pubmed: 12473605
PLoS One. 2009;4(4):e5415
pubmed: 19404404
Br J Cancer. 2014 Aug 12;111(4):646-50
pubmed: 24755886
Cancer Res. 2005 Jun 1;65(11):4633-44
pubmed: 15930281
Nat Protoc. 2006;1(1):206-14
pubmed: 17406234
Genes Cancer. 2010 Feb 1;1(2):177-187
pubmed: 20827386
PLoS One. 2017 Nov 1;12(11):e0186275
pubmed: 29091716
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3978-83
pubmed: 9108090
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5324-9
pubmed: 19289832
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10149-54
pubmed: 18626011
Cancer Cell. 2014 Nov 10;26(5):668-681
pubmed: 25453903
Nat Rev Cancer. 2017 Jun;17(6):337-351
pubmed: 28450705
Cancer Res. 2003 Jul 1;63(13):3464-8
pubmed: 12839926
Cell. 2017 Sep 21;171(1):163-178.e19
pubmed: 28844694
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):672-7
pubmed: 15701855
Cancer Res. 2009 Dec 1;69(23):9047-55
pubmed: 19920188
Cancer Cell. 2013 Feb 11;23(2):249-62
pubmed: 23410977
Nat Genet. 2017 Feb;49(2):213-222
pubmed: 27941796
PLoS One. 2011 Apr 29;6(4):e19305
pubmed: 21559395
J Natl Cancer Inst. 2011 Jun 22;103(12):962-78
pubmed: 21653923
J Clin Invest. 1997 Jan 15;99(2):239-47
pubmed: 9005992
Mol Cancer Ther. 2009 Feb;8(2):449-57
pubmed: 19190116
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Eur J Cancer. 2003 Sep;39(13):1842-51
pubmed: 12932661
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Bioinformatics. 2015 Jul 15;31(14):2382-3
pubmed: 25765347
Nature. 2000 Aug 10;406(6796):593-9
pubmed: 10949293
Sci Rep. 2016 Sep 27;6:33926
pubmed: 27671553
Neoplasia. 2011 Feb;13(2):145-53
pubmed: 21403840
Nat Struct Mol Biol. 2012 Nov;19(11):1155-60
pubmed: 23022729
Cancer Cell. 2010 Oct 19;18(4):316-28
pubmed: 20951942
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1307-16
pubmed: 25737553
Mar Drugs. 2014 Jan 27;12(2):719-33
pubmed: 24473171
Cold Spring Harb Perspect Med. 2013 Aug 01;3(8):
pubmed: 23906881
Biochemistry. 1996 Oct 15;35(41):13303-9
pubmed: 8873596
Nature. 1996 Feb 29;379(6568):844-7
pubmed: 8587611
Cancer Res. 1996 Jul 1;56(13):2945-8
pubmed: 8674046
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
J Clin Oncol. 2009 Sep 1;27(25):4188-96
pubmed: 19652065
Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):9870-9875
pubmed: 28847958
Mol Cancer Ther. 2011 Aug;10(8):1481-9
pubmed: 21622731
Eur J Cancer. 2012 Mar;48(4):579-85
pubmed: 22088484
Blood. 1996 Aug 1;88(3):1052-61
pubmed: 8704214