| 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
|
| Resource |
| Human and Animal Cells |
HuCCT1(RCB1960) |
