FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma

Yuanli Zhen, Kai Liu, Lei Shi, Simran Shah, Qin Xu, Haley Ellis, Eranga R. Balasooriya, Johannes Kreuzer, Robert Morris, Albert S. Baldwin, Dejan Juric, Wilhelm Haas and Nabeel Bardeesy ()
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Yuanli Zhen: Massachusetts General Hospital
Kai Liu: Harvard Medical School
Lei Shi: Massachusetts General Hospital
Simran Shah: Massachusetts General Hospital
Qin Xu: Massachusetts General Hospital
Haley Ellis: Massachusetts General Hospital
Eranga R. Balasooriya: Massachusetts General Hospital
Johannes Kreuzer: Massachusetts General Hospital
Robert Morris: Massachusetts General Hospital
Albert S. Baldwin: University of North Carolina at Chapel Hill School of Medicine
Dejan Juric: Massachusetts General Hospital
Wilhelm Haas: Massachusetts General Hospital
Nabeel Bardeesy: Massachusetts General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47514-y

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