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 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.
Highlights
The fibroblast growth factor receptor family comprises four functional members (FGFRs 1-4) that bind with varying affinities to 22 different fibroblast growth factor (FGF) ligands to activate downstream signaling pathways controlling cell proliferation, differentiation, vasculature, survival, and migration [1,2]
We identified a strong positive correlation between FGFR2 and FGF7 messenger ribonucleic acid (mRNA) expression in RMS cell lines with higher expression of both ligand and receptor in fusion-gene-positive rhabdomyosarcoma (FP-RMS) cells compared to fusion-negative rhabdomyosarcoma (FN-RMS) cells (Fig. S2C)
An FGF7 enzyme-linked immunosorbent assay (ELISA) revealed that two of the three small interfering ribonucleic acid (siRNA) were more effective at reducing protein upon knockdown (Fig. 4F), which was confirmed at the mRNA level by quantitative real-time PCR (qRT-PCR) (Fig. S6D). These results demonstrate that both FGF7 and FGFR2 proteins play a role in maintaining FP-RMS cell viability
Summary
The fibroblast growth factor receptor family comprises four functional members (FGFRs 1-4) that bind with varying affinities to 22 different fibroblast growth factor (FGF) ligands to activate downstream signaling pathways controlling cell proliferation, differentiation, vasculature, survival, and migration [1,2]. In this way, FGF/R signaling has been shown to control cardiac, lung and muscle development, wound healing, and embryonic patterning [3,4,5,6,7,8,9]. FGFR2 was among the highest expressed genes in a patient derived xenograft (PDX) model from a FPRMS patient heavily pretreated with chemotherapy [22]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
