Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

室管膜瘤 (EPN) 是中枢神经系统肿瘤，包括侵袭性和良性分子亚型。然而，高危亚型后颅窝A组（PF-A）和幕上RELA融合阳性（ST-RELA）的治疗仅限于大体全切除和放疗，仍缺乏有效的全身治疗理念。我们最近将成纤维细胞生长因子受体 1 和 3 ( FGFR1/FGFR3 ) 描述为 EPN 的致癌驱动因素。然而，潜在的分子机制及其作为治疗靶点的潜力尚未得到详细研究。利用 467 个 EPN 组织的转录组数据，我们发现FGFR1和FGFR3在所有分子组中广泛表达。 FGFR3 mRNA 水平在 ST-RELA 中富集，在 EPN 以及其他脑肿瘤中表达最高。我们进一步确定了所有 EPN 亚型中成纤维细胞生长因子 1 和 2（ FGF1 、 FGF2）的高表达水平，而FGF9在 ST-EPN 中升高。对我们的 EPN 单细胞 RNA 测序数据的询问表明， FGFR3在循环和祖细胞样细胞群中进一步富集。佐证的是，我们发现FGFR3主要在小鼠胚胎和人脑数据集中的放射状胶质细胞中表达。此外，我们检测到FGFR1/3-IIIc变体的选择性剪接，已知该变体可增强配体亲和力和 FGFR 信号传导。在 PF-A 和 ST-RELA 细胞模型中，FGFR1/3 激活的显性失活中断证明了对关键致癌途径的抑制，导致细胞生长和干细胞特征减少。 为了探索治疗靶向 FGFR 的可行性，我们在 12 个患者来源的 EPN 细胞模型中测试了一组 FGFR 抑制剂，揭示了低微摩尔至纳摩尔范围的敏感性。最后，我们获得了 FGFR 抑制剂尼达尼布在治疗复发性 ST-RELA 患者中的活性的第一个临床证据。总之，这些临床前和临床数据表明 FGFR 抑制是对抗侵袭性 EPN 的一种新颖且可行的方法。