Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance and Progression of Fusion-Positive Rhabdomyosarcoma

作者：Salah Boudjadi, Hana Kim, Bishwanath Chatterjee, Pawan Kumar Raut, Thanh Nguyen, Puspa Raj Pandey, Reyaz ur Rasool, Wenyue Sun, Frederic G. Barr · 发表于：Molecular Cancer Therapeutics · 年份：2025 · DOI：10.1158/1535-7163.mct-24-0328 · 被引用次数：2 · 研究领域：Fibroblast Growth Factor Research、Sarcoma Diagnosis and Treatment、Tuberous Sclerosis Complex Research

We previously used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to show that FGF8, a PAX3-FOXO1 (P3F) transcriptional target, is required for P3F-driven tumorigenicity and, when aberrantly expressed, can maintain tumorigenicity in P3F-independent recurrent tumors. We report in this study that FGF8, FGFR1, and FGFR4 are often highly expressed in FP-RMS tumors. High FGF8 expression in FP-RMS cells is associated with high sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Although downregulating FGF8 resulted in loss of sensitivity to these inhibitors, FGF8 upregulation in myoblasts decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. FGF8 downregulation of FGFR4 expression was reverted by inhibitors of FGFR1, MEK, or ERK, thus defining a signaling pathway by which FGF8 mediates this regulatory effect. Finally, high FGF8 expression in P3F-independent recurrent tumors was attributable to a rearrangement of viral long terminal repeat (LTR) sequences into the FGF8 3' untranslated region, resulting in increased FGF8 mRNA stability. These findings indicate that FGF8 exerts oncogenic effects in FP-RMS via FGFR4 and may exert oncogenic effects in P3F-independent relapses via FGFR1. Our study reveals the functional significance of FGF8 in FP-RMS and provides a rationale for preclinical studies of FGFR inhibitors in FP-RMS.