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

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.

Immunoreactivity against fibroblast growth factor 8 in alveolar rhabdomyosarcoma patients and its involvement in tumor aggressiveness

“…In contrast, FGF18, the third member of the FGF8 subfamily and a prognostic marker in some of the most aggressive adult epithelial cancers, 34 , 35 was not expressed in RMS cells at all. Expression of FGF7 in PF + ARMS cells was also significantly higher compared to PF−ERMS cells ( p = 0,015), as recently reported by others, 36 but similar to that measured in normal cells. FGF1 and FGF2, instead, two important family members with broad mitogenic activities in normal and pathological conditions, were expressed in tumor cell lines as much as in normal cells.…”

An m6A/m5C/m1A/m7G-Related Long Non-coding RNA Signature to Predict Prognosis and Immune Features of Glioma

“…Sensitivity to A.770041, AMG.706, ABT.888, AP.24534, AS601245, AUY922, and AZ628 was higher in the low-risk group than the high-risk group, while sensitivity to axitinib, A.443654, AG.014699, AICAR, Akt inhibitor VIII, and ATRA was higher in the high-risk group than the low-risk group. These drugs are commonly used in the clinical treatment of gliomas, and our results support their therapeutic value in this context ( Djuzenova et al, 2012 ; Yuan et al, 2018 ; Wang et al, 2021c ; Milton et al, 2021 ). In addition, these findings suggest the prospect of targeting lncRNAs in therapy for patients with gliomas.…”

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…Preliminary results of Dovitinib in NB cells, which express high levels of FGFR, indicated anticancer-activity in this tumor type [ 741 ]. Similar results were reported for RMS, albeit it was demonstrated that this inhibitor is not as potent as other FGFR inhibitors (i.e., ponatinib) [ 656 , 742 ]. In addition, due to its ability to cross the BBB, this compound has been indicated as a suitable candidate for the treatment of CNS tumors.…”

“…Considering pediatric tumors, nintedanib has been shown to inhibit growth in EWS (A673, CHP100) and OS (SaOS2) cell lines, with a key role in controlling OS lung metastatic growth by blocking the fibrogenic reprogramming of OS stem cells (OSCs) [ 654 , 655 ]. Growth inhibition was also observed in a panel of 13 RMS cells, with the PAX3–FOXO1 fusion-gene-positive ones more sensitive to treatment [ 656 ]. Moreover, there are reports of EPN cells being sensitive to nintedanib treatment, while this drug is able to extend the survival of mice bearing ST-RELA xenografts [ 657 , 658 ].…”