Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

激活成纤维细胞生长因子受体 2 （FGFR2） 的基因组改变在肝内胆管癌 （ICC） 中很常见，并赋予对 FGFR 抑制的敏感性。然而，反应的深度和持续时间通常是有限的。在这里，我们对患者来源的模型进行综合转录组学、代谢组学和磷酸化蛋白质组学分析，以确定促进 ICC 生长的致癌 FGFR2 信号转导下游的途径，并揭示与途径抑制相关的代偿机制。我们发现 FGFR2 介导的核因子-κB （NF-κB） 激活保持高度糖酵解表型。相反，FGFR 抑制阻断葡萄糖摄取和糖酵解，同时刺激适应性变化，包括改变有利于脂肪酸氧化的燃料源利用和增加线粒体融合和自噬。因此，线粒体联合靶向增强了 FGFR 抑制剂的疗效，这种效果在异种移植模型中通过间歇性禁食得到增强。因此，我们表明致癌 FGFR2 信号传导驱动 ICC 中 NF-κB 依赖性糖酵解，并且响应 FGFR 抑制的代谢重编程赋予了新的靶向脆弱性。