FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.
Détails
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_6F675513FACC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.
Périodique
Molecular oncology
ISSN
1878-0261 (Electronic)
ISSN-L
1574-7891
Statut éditorial
Publié
Date de publication
03/2022
Peer-reviewed
Oui
Volume
16
Numéro
6
Pages
1272-1289
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Rhabdomyosarcomas are aggressive pediatric soft-tissue sarcomas and include high-risk PAX3-FOXO1 fusion-gene-positive cases. Fibroblast growth factor receptor 4 (FGFR4) is known to contribute to rhabdomyosarcoma progression; here, we sought to investigate the involvement and potential for therapeutic targeting of other FGFRs in this disease. Cell-based screening of FGFR inhibitors with potential for clinical repurposing (NVP-BGJ398, nintedanib, dovitinib, and ponatinib) revealed greater sensitivity of fusion-gene-positive versus fusion-gene-negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. Furthermore, patient samples exhibit higher mRNA levels of FGFR2 and FGF7 in fusion-gene-positive versus fusion-gene-negative rhabdomyosarcomas. Sustained intracellular mitogen-activated protein kinase (MAPK) activity and FGF7 secretion into culture media during serum starvation of PAX3-FOXO1 rhabdomyosarcoma cells together with decreased cell viability after genetic silencing of FGFR2 or FGF7 was in keeping with a novel FGF7-FGFR2 autocrine loop. FGFR inhibition with NVP-BGJ398 reduced viability and was synergistic with SN38, the active metabolite of irinotecan. In vivo, NVP-BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion-gene-positive rhabdomyosarcomas.
Mots-clé
Autocrine Communication, Cell Line, Tumor, Child, Drug Resistance, Neoplasm, Fibroblast Growth Factor 7, Humans, Irinotecan, Protein Kinase Inhibitors/pharmacology, Receptor, Fibroblast Growth Factor, Type 2, Rhabdomyosarcoma/drug therapy, Rhabdomyosarcoma/genetics, FGF7, FGFR2, NVP-BGJ398, autocrine loop, fibroblast growth factor receptor, rhabdomyosarcoma
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/09/2023 9:53
Dernière modification de la notice
22/01/2024 9:41