Metabolic Plasticity of IDH1- Mutant Glioma Cell Lines Is Responsible for Low Sensitivity to Glutaminase Inhibition

Abstract

Targeting glutamine metabolism in cancer has become increasingly vibrant area of research. Mutant IDH1 (IDH1^mut) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG). Here, we report the adaptability of IDH1^mut cells’ metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 showed decreased production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1^mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. The major metabolic adaptation involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1^mut gliomas.

Keywords: IDH1-mutant, gliomas, glutaminase, CB839, AGI5198, 13C tracing