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Published on: March 11, 2017
FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
Yuanli Zhen1,2,3,4, Kai Liu5, Lei Shi1,2,3,4
1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
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.
Insights
Targeting Fibroblast Growth Factor Receptor 2 (FGFR2) in intrahepatic cholangiocarcinoma (ICC) shows promise. This study reveals how FGFR2 fuels ICC growth via glycolysis and identifies metabolic vulnerabilities for enhanced treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Metabolomics
Background:
- Genomic alterations activating Fibroblast Growth Factor Receptor 2 (FGFR2) are prevalent in intrahepatic cholangiocarcinoma (ICC).
- While FGFR inhibition shows sensitivity, responses are often limited in depth and duration.
Purpose of the Study:
- To define downstream pathways of oncogenic FGFR2 signaling in ICC using integrative multi-omics.
- To uncover compensatory metabolic mechanisms during FGFR inhibition.
- To identify novel therapeutic vulnerabilities in ICC.
Main Methods:
- Integrative transcriptomics, metabolomics, and phosphoproteomics analysis.
- Utilized patient-derived models of intrahepatic cholangiocarcinoma.
- Investigated effects of FGFR inhibition and combined therapies in xenograft models.
Main Results:
- Oncogenic FGFR2 signaling activates Nuclear factor-κB (NF-κB), promoting a glycolytic phenotype in ICC.
- FGFR inhibition reduces glucose uptake and glycolysis, inducing adaptive metabolic reprogramming towards fatty acid oxidation and increased mitochondrial activity.
- Combined FGFR inhibition and mitochondrial targeting potentiated efficacy, further enhanced by intermittent fasting in vivo.
Conclusions:
- Oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC.
- Metabolic reprogramming occurs in response to FGFR inhibition, presenting new targetable vulnerabilities.
- Combination therapies targeting metabolism may overcome resistance to FGFR inhibitors in ICC.
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