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dc.contributor.authorMilton, CI
dc.contributor.authorSelfe, J
dc.contributor.authorAladowicz, E
dc.contributor.authorMan, SYK
dc.contributor.authorBernauer, C
dc.contributor.authorMissiaglia, E
dc.contributor.authorWalters, ZS
dc.contributor.authorGatz, SA
dc.contributor.authorKelsey, A
dc.contributor.authorGenerali, M
dc.contributor.authorBox, G
dc.contributor.authorValenti, M
dc.contributor.authorde Haven-Brandon, A
dc.contributor.authorGaliwango, D
dc.contributor.authorHayes, A
dc.contributor.authorClarke, M
dc.contributor.authorIzquierdo, E
dc.contributor.authorGonzalez De Castro, D
dc.contributor.authorRaynaud, FI
dc.contributor.authorKirkin, V
dc.contributor.authorShipley, JM
dc.date.accessioned2022-02-18T11:19:55Z
dc.date.available2022-02-18T11:19:55Z
dc.date.issued2021-11-30
dc.identifier.citationMolecular oncology, 2021
dc.identifier.issn1574-7891
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5018
dc.identifier.eissn1878-0261
dc.identifier.eissn1878-0261
dc.identifier.doi10.1002/1878-0261.13145
dc.identifier.doi10.1002/1878-0261.13145
dc.description.abstractRhabdomyosarcomas 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.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.publisherWILEY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleFGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.
dc.typeJournal Article
dcterms.dateAccepted2021-11-29
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1002/1878-0261.13145
rioxxterms.licenseref.startdate2021-11-30
dc.relation.isPartOfMolecular oncology
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
icr.researchteamSarcoma Molecular Pathology
dc.contributor.icrauthorSelfe, Joanna
dc.contributor.icrauthorBernauer, Carolina
dc.contributor.icrauthorClarke, Matthew
dc.contributor.icrauthorRaynaud, Florence
dc.contributor.icrauthorShipley, Janet


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