Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor.
Adolescent
Adult
Animals
Benzamides
/ pharmacology
Cell Line, Tumor
Child
Desmoplastic Small Round Cell Tumor
/ drug therapy
Female
Gene Expression Regulation, Neoplastic
Humans
Indazoles
/ pharmacology
Male
Mice
Oncogene Proteins, Fusion
/ genetics
RNA-Binding Protein EWS
/ antagonists & inhibitors
Receptor, trkC
/ genetics
WT1 Proteins
/ genetics
Xenograft Model Antitumor Assays
Young Adult
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 02 2021
15 02 2021
Historique:
received:
01
07
2020
revised:
27
08
2020
accepted:
18
11
2020
pubmed:
25
11
2020
medline:
21
1
2022
entrez:
24
11
2020
Statut:
ppublish
Résumé
Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program. Among these neural markers, we found prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target We found that EWSR1-WT1 binds upstream of Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both
Identifiants
pubmed: 33229458
pii: 1078-0432.CCR-20-2585
doi: 10.1158/1078-0432.CCR-20-2585
pmc: PMC8212565
mid: NIHMS1649687
doi:
Substances chimiques
Benzamides
0
EWSR1 protein, human
0
Indazoles
0
NTRK3 protein, human
0
Oncogene Proteins, Fusion
0
RNA-Binding Protein EWS
0
WT1 Proteins
0
WT1 protein, human
0
Receptor, trkC
EC 2.7.10.1
entrectinib
L5ORF0AN1I
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1184-1194Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA217694
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222856
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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