RRC ID 79180
Author Zhen Y, Liu K, Shi L, Shah S, Xu Q, Ellis H, Balasooriya ER, Kreuzer J, Morris R, Baldwin AS, Juric D, Haas W, Bardeesy N.
Title FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
Journal Nat Commun
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.
Volume 15(1)
Pages 3805
Published 2024-5-7
DOI 10.1038/s41467-024-47514-y
PII 10.1038/s41467-024-47514-y
PMID 38714664
PMC PMC11076599
MeSH Animals Autophagy / drug effects Bile Duct Neoplasms* / drug therapy Bile Duct Neoplasms* / genetics Bile Duct Neoplasms* / metabolism Bile Duct Neoplasms* / pathology Cell Line, Tumor Cholangiocarcinoma* / drug therapy Cholangiocarcinoma* / genetics Cholangiocarcinoma* / metabolism Cholangiocarcinoma* / pathology Gene Expression Regulation, Neoplastic / drug effects Glucose* / metabolism Glycolysis* / drug effects Humans Mice Mitochondria / drug effects Mitochondria / metabolism NF-kappa B* / metabolism Pyrimidines / pharmacology Receptor, Fibroblast Growth Factor, Type 2* / antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 2* / genetics Receptor, Fibroblast Growth Factor, Type 2* / metabolism Signal Transduction* / drug effects Xenograft Model Antitumor Assays
Human and Animal Cells HuCCT1(RCB1960)