2. Academic Validation
  3. FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma

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

  • Nat Commun. 2024 May 7;15(1):3805. doi: 10.1038/s41467-024-47514-y.
Yuanli Zhen 1 2 3 4,  Kai Liu 5,  Lei Shi 1 2 3 4,  Simran Shah 1,  Qin Xu 1 2 3 4,  Haley Ellis 1 2 3 4,  Eranga R Balasooriya 1 2 3 4,  Johannes Kreuzer 1 3,  Robert Morris 1,  Albert S Baldwin 6,  Dejan Juric 1 3,  Wilhelm Haas 1 3,  Nabeel Bardeesy 7 8 9 10
Affiliations

Affiliations

  • 1 Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • 2 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 3 Dept. of Medicine, Harvard Medical School, Boston, MA, USA.
  • 4 The Cancer Program, Broad Institute, Cambridge, MA, USA.
  • 5 Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, USA.
  • 7 Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu.
  • 8 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu.
  • 9 Dept. of Medicine, Harvard Medical School, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu.
  • 10 The Cancer Program, Broad Institute, Cambridge, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu.
PMID: 38714664 DOI: 10.1038/s41467-024-47514-y
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.

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