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Targeting pancreatic cancer metabolic dependencies through glutamine antagonism
Joel Encarnación-Rosado1,2, Albert S W Sohn1,2, Douglas E Biancur1,2
1Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
Insights
Targeting glutamine metabolism in pancreatic cancer with DON or its pro-drug DRP-104 caused a metabolic crisis. Combining DRP-104 with an ERK inhibitor significantly improved survival in pancreatic ductal adenocarcinoma models.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer cell biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) relies on glutamine (Gln) for proliferation and redox balance.
- Previous attempts to inhibit Gln metabolism faced challenges due to rapid metabolic reprogramming and therapeutic resistance.
Purpose of the Study:
- To investigate the efficacy of glutamine antagonists in PDAC.
- To explore combination therapies for improved treatment outcomes in PDAC.
Main Methods:
- In vitro treatment of PDAC cells with 6-diazo-5-oxo-L-norleucine (DON).
- In vivo studies using sirpiglenastat (DRP-104), a DON pro-drug, in PDAC models.
- Analysis of extracellular signal-regulated kinase (ERK) signaling pathways.
- Combinatorial treatment with DRP-104 and trametinib (ERK inhibitor).
Main Results:
- DON induced a significant metabolic crisis in PDAC cells in vitro.
- DRP-104 demonstrated profound tumor growth inhibition in vivo.
- ERK signaling was identified as a compensatory mechanism activated by Gln antagonism.
- Combination therapy with DRP-104 and trametinib significantly increased survival in a syngeneic PDAC model.
Conclusions:
- Targeting glutamine metabolism represents a potential therapeutic strategy for PDAC.
- Combination therapy involving glutamine antagonism and ERK pathway inhibition may enhance therapeutic efficacy in PDAC.
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