Children with aggressive pediatric solid tumors have poor outcomes and novel treatments are needed. Pediatric solid tumors demonstrate aberrant expression and activity of the fibroblast growth factor receptor (FGFR) family, suggesting FGFR inhibitors may be effective therapeutic agents. AZD4547 is a multikinase inhibitor of the FGFR1-3 kinases, and we hypothesized that AZD4547 would be effective in pediatric solid tumor preclinical models. We evaluated the effects of AZD4547 on neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma cells alone and in combination with STAT3 inhibition. Continuous live cell imaging was used to measure induction of apoptosis and effects on migration. Receptor inhibition and intracellular signaling were examined by western blotting. AZD4547 treatment resulted in decreased cell confluence, increased apoptosis and reduced cell migration in all tested cell lines. AZD4547 treatment led to decreased phosphorylation of signaling proteins involved in cell survival and apoptotic pathways and increased phosphorylation of STAT3, and treatment of cell lines with AZD4547 combined with STAT3 inhibition demonstrated increased efficacy. Sensitivity to AZD4547 appears to be mediated by effects on the Ras/MAPK and JAK/STAT pathways, and AZD4547 represents a potential novel therapeutic agent for children with solid tumors.

中文翻译：

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FGFR1-3 抑制剂 AZD4547 在儿科实体瘤模型中的功效机制。

患有侵袭性小儿实体瘤的儿童预后不佳，需要新的治疗方法。小儿实体瘤表现出成纤维细胞生长因子受体 (FGFR) 家族的异常表达和活性，表明 FGFR 抑制剂可能是有效的治疗剂。AZD4547 是 FGFR1-3 激酶的多激酶抑制剂，我们假设 AZD4547 在儿科实体瘤临床前模型中有效。我们评估了 AZD4547 对神经母细胞瘤、横纹肌肉瘤和尤文肉瘤细胞的单独作用以及与 STAT3 抑制联合作用的作用。连续活细胞成像用于测量细胞凋亡的诱导和对迁移的影响。通过蛋白质印迹检查受体抑制和细胞内信号传导。AZD4547处理导致细胞融合减少，在所有测试的细胞系中增加细胞凋亡并减少细胞迁移。AZD4547 处理导致参与细胞存活和凋亡途径的信号蛋白磷酸化减少，STAT3 磷酸化增加，并且用 AZD4547 联合 STAT3 抑制处理细胞系显示出更高的功效。对 AZD4547 的敏感性似乎是由对 Ras/MAPK 和 JAK/STAT 通路的影响介导的，AZD4547 代表了一种潜在的儿童实体瘤新型治疗剂。