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RESEARCH

Open Access

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition Victor Ruiz-Rodado1, Adrian Lita1, Tyrone Dowdy1, Orieta Celiku1, Alejandra Cavazos Saldana1, Herui Wang1, Chun Zhang Yang1, Raj Chari2, Aiguo Li1, Wei Zhang1, Hua Song1, Meili Zhang1, Susie Ahn1, Dionne Davis1, Xiang Chen3, Zhengping Zhuang1, Christel Herold-Mende4, Kylie J. Walters3, Mark R. Gilbert1 and Mioara Larion1*

Abstract Background: Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1mut) 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). Methods: We have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-offunction (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity. Results: We report the adaptability of IDH1mut cells’ metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the 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 IDH1mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. Conclusions: Major metabolic adaptations 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 IDH1mut gliomas. Keywords: IDH1-mutant, Gliomas, Glutaminase, CB839, AGI5198, 13C tracing

Background Isocitrate dehydrogenase I gene (IDH1) mutations occur in up to 80% of low-grade (WHO grade II) gliomas and about 5% of all glioblastomas (GBM) [1, 2]. IDH1 is also mutated in acute myeloid leukemia (AML) [3], cholangiocarcinomas, melanomas, chondrosarcomas, fibrosarcoma, * Correspondence: [email protected] 1 Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Building 37, Room 1136A, Bethesda, Maryland, USA Full list of author information is available at the end of the article

and other malignancies [4–6]. Despite being one of the few examples of a metabolic enzyme’s mutation linked directly to cancer and its prevalence, the contribution of IDH1mut enzyme activity to global tumor metabolism and its involvement in oncogenesis are not fully understood. The substitution of an arginine to a histidine (R132H) is the most common mutation (90%), and occurs in the active site of the enzyme leading to formation of 2hydroxyglutarat