Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors.
Animals
Antineoplastic Agents
/ pharmacology
CRISPR-Cas Systems
Cell Line, Tumor
Female
HEK293 Cells
Humans
Mice
Mice, Nude
Mutation
Protein Kinase Inhibitors
/ pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ antagonists & inhibitors
Rhabdoid Tumor
/ drug therapy
Small Molecule Libraries
/ pharmacology
PTPN11
SMARCB1
genome-wide CRISPR screening
high-throughput drug screening
receptor tyrosine kinase
rhabdoid tumors
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
27 08 2019
27 08 2019
Historique:
received:
17
07
2017
revised:
19
04
2019
accepted:
08
07
2019
entrez:
29
8
2019
pubmed:
29
8
2019
medline:
26
8
2020
Statut:
ppublish
Résumé
Cancer is often seen as a disease of mutations and chromosomal abnormalities. However, some cancers, including pediatric rhabdoid tumors (RTs), lack recurrent alterations targetable by current drugs and need alternative, informed therapeutic options. To nominate potential targets, we performed a high-throughput small-molecule screen complemented by a genome-scale CRISPR-Cas9 gene-knockout screen in a large number of RT and control cell lines. These approaches converged to reveal several receptor tyrosine kinases (RTKs) as therapeutic targets, with RTK inhibition effective in suppressing RT cell growth in vitro and against a xenograft model in vivo. RT cell lines highly express and activate (phosphorylate) different RTKs, creating dependency without mutation or amplification. Downstream of RTK signaling, we identified PTPN11, encoding the pro-growth signaling protein SHP2, as a shared dependency across all RT cell lines. This study demonstrates that large-scale perturbational screening can uncover vulnerabilities in cancers with "quiet" genomes.
Identifiants
pubmed: 31461650
pii: S2211-1247(19)30911-8
doi: 10.1016/j.celrep.2019.07.021
pmc: PMC7319190
mid: NIHMS1597211
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Small Molecule Libraries
0
PTPN11 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
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
2331-2344.e8Subventions
Organisme : NCI NIH HHS
ID : U01 CA176152
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA113794
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA183558
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176058
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217848
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172152
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Références
PLoS One. 2014 Mar 20;9(3):e92146
pubmed: 24651269
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Lancet Oncol. 2015 May;16(5):569-82
pubmed: 25882982
Nucleic Acids Res. 2017 Jun 20;45(11):6442-6458
pubmed: 28431046
Biochem J. 2007 Aug 15;406(1):57-66
pubmed: 17506723
Genome Biol. 2014;15(12):550
pubmed: 25516281
Clin Cancer Res. 2004 Sep 1;10(17):5940-8
pubmed: 15355927
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Oncogene. 2002 Aug 8;21(34):5193-203
pubmed: 12149641
Nat Immunol. 2015 Jul;16(7):775-84
pubmed: 25985234
Cancer Res. 2007 Mar 1;67(5):2081-8
pubmed: 17332337
Breast Cancer Res. 2016 Jan 04;18(1):2
pubmed: 26728598
Cancer Cell. 2016 Dec 12;30(6):891-908
pubmed: 27960086
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Nature. 2013 Jul 11;499(7457):214-218
pubmed: 23770567
Cancer Res. 2009 May 1;69(9):3937-46
pubmed: 19366796
J Clin Invest. 2012 Aug;122(8):2983-8
pubmed: 22797305
Cancer Res. 2010 Mar 1;70(5):1854-65
pubmed: 20179200
Nat Biotechnol. 2016 Apr;34(4):419-23
pubmed: 26928769
Cell Rep. 2014 Nov 6;9(3):829-41
pubmed: 25437539
In Vitro Cell Dev Biol Anim. 2003 Jul-Aug;39(7):288-90
pubmed: 14609362
Nat Commun. 2017 Mar 06;8:14648
pubmed: 28262751
Leukemia. 2003 Jan;17(1):120-4
pubmed: 12529668
Biochem Biophys Res Commun. 2010 Apr 16;394(4):1042-6
pubmed: 20331976
Cancer Res. 2009 Oct 15;69(20):8094-101
pubmed: 19789351
Leuk Lymphoma. 2005 Feb;46(2):247-55
pubmed: 15621809
Mol Cancer. 2015 Sep 15;14:167
pubmed: 26370283
Nat Genet. 2017 Nov;49(11):1613-1623
pubmed: 28945250
Nat Chem Biol. 2016 Feb;12(2):109-16
pubmed: 26656090
Lab Invest. 2010 May;90(5):724-38
pubmed: 20212451
Leukemia. 2018 Jan;32(1):203-213
pubmed: 28804122
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Cancer Cell. 2016 Mar 14;29(3):394-406
pubmed: 26977886
Cancer Biol Ther. 2009 Nov;8(21):2042-50
pubmed: 19755855
Nucleic Acids Res. 2010 Dec;38(22):e204
pubmed: 20929874
Cancer Discov. 2016 Aug;6(8):914-29
pubmed: 27260156
Hum Mol Genet. 2013 Feb 15;22(4):795-803
pubmed: 23175443
Nature. 2016 Jul 7;535(7610):148-52
pubmed: 27362227
Oncogene. 2001 Jun 14;20(27):3553-62
pubmed: 11429702
Nat Methods. 2019 Mar;16(3):243-245
pubmed: 30742040
Oncogene. 1997 Aug 14;15(7):817-26
pubmed: 9266968
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13796-800
pubmed: 11095756
Nat Biotechnol. 2011 Oct 30;29(11):1046-51
pubmed: 22037378
Nat Commun. 2016 Jan 28;7:10421
pubmed: 26818002
Genome Res. 2011 Oct;21(10):1650-8
pubmed: 21795385
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7830-5
pubmed: 12808148
Oncogene. 2014 Jun 5;33(23):3024-32
pubmed: 23851500
Cell Rep. 2016 Oct 25;17(5):1265-1275
pubmed: 27783942
Pediatr Blood Cancer. 2013 Jul;60(7):1095-102
pubmed: 23382118
Nat Genet. 2017 Feb;49(2):296-302
pubmed: 27941798
Nat Genet. 2017 Dec;49(12):1779-1784
pubmed: 29083409
Cell Rep. 2015 Sep 29;12(12):1978-85
pubmed: 26365186
Br J Cancer. 2014 Mar 4;110(5):1169-78
pubmed: 24518603
Cancer Discov. 2016 Aug;6(8):900-13
pubmed: 27260157
PLoS One. 2013 Oct 30;8(10):e77652
pubmed: 24204904
Cancer Discov. 2015 Nov;5(11):1210-23
pubmed: 26482930
PLoS One. 2014 Jun 26;9(6):e98515
pubmed: 24968263
Nat Genet. 2017 Feb;49(2):289-295
pubmed: 27941797
Cancer Cell. 2016 Mar 14;29(3):379-393
pubmed: 26923874
Sci Data. 2014 Sep 30;1:140035
pubmed: 25984343
Cancer Res. 2009 Jun 1;69(11):4613-20
pubmed: 19458078
Cell Rep. 2017 Nov 14;21(7):1737-1745
pubmed: 29141209
Sci Transl Med. 2010 Dec 15;2(62):62ra93
pubmed: 21160078