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

Author

Listed:
  • Yuanli Zhen

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute)

  • Kai Liu

    (Harvard Medical School)

  • Lei Shi

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute)

  • Simran Shah

    (Massachusetts General Hospital)

  • Qin Xu

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute)

  • Haley Ellis

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute)

  • Eranga R. Balasooriya

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute)

  • Johannes Kreuzer

    (Massachusetts General Hospital
    Harvard Medical School)

  • Robert Morris

    (Massachusetts General Hospital)

  • Albert S. Baldwin

    (University of North Carolina at Chapel Hill School of Medicine)

  • Dejan Juric

    (Massachusetts General Hospital
    Harvard Medical School)

  • Wilhelm Haas

    (Massachusetts General Hospital
    Harvard Medical School)

  • Nabeel Bardeesy

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute)

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.

Suggested Citation

  • 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 & Nabeel Bardeesy, 2024. "FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47514-y
    DOI: 10.1038/s41467-024-47514-y
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