FGF7–FGFR2 autocrine signaling increases growth and chemoresistance of fusion‐positive rhabdomyosarcomas

Christopher I Milton, Joanna Selfe, Ewa Aladowicz, Y.K. Stella Man, Carolina Bernauer, Edoardo Missiaglia, Zoë S Walters, Susanne A Gatz, Anna Kelsey, Melanie Generali, Gary Box, Melanie Valenti, Alexis Haven‐Brandon, David Galiwango, Angela Hayes, Matthew Clarke, Elisa Izquierdo, David Gonzalez De Castro, Florence I. Raynaud, Vladimir KirkinJanet M Shipley

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Abstract

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 -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 -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 SN-38, 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.
Original languageEnglish
JournalMolecular oncology
Early online date30 Nov 2021
DOIs
Publication statusEarly online date - 30 Nov 2021

Keywords

  • Cancer Research
  • Genetics
  • Molecular Medicine
  • General Medicine
  • Oncology

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