Rhabdoid Tumors Are Sensitive to the Protein-Translation Inhibitor Homoharringtonine.
Animals
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Neoplasm
/ genetics
Female
Gene Expression Regulation, Neoplastic
Homoharringtonine
/ pharmacology
Humans
Mice
Protein Biosynthesis
/ drug effects
Rhabdoid Tumor
/ drug therapy
Xenograft Model Antitumor Assays
bcl-X Protein
/ genetics
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:
15 09 2020
15 09 2020
Historique:
received:
18
08
2019
revised:
30
05
2020
accepted:
29
06
2020
pubmed:
8
7
2020
medline:
15
12
2021
entrez:
8
7
2020
Statut:
ppublish
Résumé
Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit We screened eight rhabdoid tumor cell lines with 481 small molecules and compared their sensitivity with that of 879 other cancer cell lines. Genome-scale CRISPR-Cas9 inactivation screens in rhabdoid tumors were analyzed to confirm target vulnerabilities. Gene expression and CRISPR-Cas9 data were queried across cell lines and primary rhabdoid tumors to discover biomarkers of small-molecule sensitivity. Molecular correlates were validated by manipulating gene expression. Subcutaneous rhabdoid tumor xenografts were treated with the most effective drug to confirm Small-molecule screening identified the protein-translation inhibitor homoharringtonine (HHT), an FDA-approved treatment for chronic myelogenous leukemia (CML), as the sole drug to which all rhabdoid tumor cell lines were selectively sensitive. Validation studies confirmed the sensitivity of rhabdoid tumor to HHT was comparable with that of CML cell lines. Low expression of the antiapoptotic gene Rhabdoid tumor cell lines and xenografts are highly sensitive to HHT, at least partially due to their low expression of
Identifiants
pubmed: 32631955
pii: 1078-0432.CCR-19-2717
doi: 10.1158/1078-0432.CCR-19-2717
pmc: PMC7501142
mid: NIHMS1609734
doi:
Substances chimiques
BCL2L1 protein, human
0
bcl-X Protein
0
Homoharringtonine
6FG8041S5B
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
4995-5006Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM007226
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA101942
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA197640
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA113794
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176058
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172152
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
Références
J Clin Invest. 2012 Aug;122(8):2983-8
pubmed: 22797305
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Cell Rep. 2014 Nov 6;9(3):829-41
pubmed: 25437539
Cancer. 2015 May 15;121(10):1637-44
pubmed: 25586015
Nat Commun. 2019 Apr 23;10(1):1881
pubmed: 31015438
Eur J Biochem. 1977 Jan;72(2):323-30
pubmed: 319998
Am J Hematol. 2019 Jan;94(1):74-79
pubmed: 30328139
Cancer Biol Ther. 2009 Mar;8(5):412-6
pubmed: 19305156
Nat Biotechnol. 2018 Feb;36(2):179-189
pubmed: 29251726
J Cell Physiol. 2016 Sep;231(9):1932-40
pubmed: 26680268
Nat Biotechnol. 2017 May;35(5):463-474
pubmed: 28319085
Cell Rep. 2017 Nov 14;21(7):1737-1745
pubmed: 29141209
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Cancer Res. 1999 Jan 1;59(1):74-9
pubmed: 9892189
Cancer Cell. 2002 Nov;2(5):415-25
pubmed: 12450796
Cancer. 2010 Dec 15;116(24):5725-32
pubmed: 20737418
Lancet Oncol. 2015 May;16(5):569-82
pubmed: 25882982
Biochim Biophys Acta. 2013 Dec;1833(12):2980-2987
pubmed: 23954445
Pediatr Blood Cancer. 2013 Jun;60(6):994-1000
pubmed: 23255438
Cancer Res. 2019 May 1;79(9):2404-2414
pubmed: 30755442
Nat Chem Biol. 2016 Feb;12(2):109-16
pubmed: 26656090
J Mol Biol. 2009 May 29;389(1):146-56
pubmed: 19362093
Am J Hum Genet. 1999 Nov;65(5):1342-8
pubmed: 10521299
Cancer Cell. 2016 Mar 14;29(3):394-406
pubmed: 26977886
Cell Death Differ. 2018 Jan;25(1):65-80
pubmed: 29149100
Cell Rep. 2019 Aug 27;28(9):2331-2344.e8
pubmed: 31461650
Cancer Discov. 2016 Aug;6(8):914-29
pubmed: 27260156
Cancer. 2017 Feb 15;123(4):682-687
pubmed: 27861763
Dev Biol. 2016 Mar 15;411(2):287-293
pubmed: 26068307
Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361
pubmed: 27899662
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13796-800
pubmed: 11095756
Blood. 2011 Jan 6;117(1):156-64
pubmed: 20971952
Leukemia. 2009 Aug;23(8):1446-54
pubmed: 19322212
Nature. 1998 Jul 9;394(6689):203-6
pubmed: 9671307
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cancer. 2001 Sep 15;92(6):1591-605
pubmed: 11745238
Pediatr Blood Cancer. 2012 Dec 15;59(7):1155-7
pubmed: 22997201
J Hematol Oncol. 2014 Jan 03;7:2
pubmed: 24387717
Mol Pharmacol. 1975 Sep;11(5):511-9
pubmed: 1237080
Mol Pharmacol. 2011 Jun;79(6):1072-83
pubmed: 21415308
Hematology. 2004 Aug;9(4):259-70
pubmed: 15621733
Front Med. 2019 Jun;13(3):378-387
pubmed: 30635781
Cancer Discov. 2015 Nov;5(11):1210-23
pubmed: 26482930
Clin Cancer Res. 2014 Apr 1;20(7):1735-40
pubmed: 24501394
Cancer Med. 2016 Aug;5(8):1765-75
pubmed: 27228363
Leukemia. 2011 Jun;25(6):985-94
pubmed: 21468038
Nat Genet. 2013 Jun;45(6):592-601
pubmed: 23644491
Cancer Cell. 2016 Mar 14;29(3):379-393
pubmed: 26923874