Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.
Joel Encarnación-RosadoAlbert S W SohnDouglas E BiancurElaine Y LinVictoria Osorio-VasquezTori RodrickDiana González-BaergaEnde ZhaoYumi YokoyamaDiane M SimeoneDrew R JonesSeth J ParkerRobert WildAlec C KimmelmanPublished in: Nature cancer (2023)
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.
Keyphrases
- signaling pathway
- induced apoptosis
- pi k akt
- cell cycle arrest
- cell proliferation
- oxidative stress
- endoplasmic reticulum stress
- cancer therapy
- public health
- transcription factor
- autism spectrum disorder
- tyrosine kinase
- intellectual disability
- combination therapy
- quantum dots
- free survival
- psychometric properties
- adverse drug
- anti inflammatory