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

36 Pages Posted: 17 May 2019 Publication Status: Review Complete

See all articles by Victor Ruiz-Rodado

Victor Ruiz-Rodado

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Adrian Lita

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Tyrone Dowdy

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Orieta Celiku

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Alejandra Cavazos-Saldana

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Herui Wang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Aiguo Li

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Wei Zhang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Hua Song

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Meili Zhang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Susie Ahn

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Dionne Davis

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Xiang Chen

National Cancer Institute at Frederick, Center for Cancer Research, Structural Biophysics Laboratory

Zhengping Zhuang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch; National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS), Surgical Neurology Branch

Christel Herold-Mende

Heidelberg University - Division of Neurosurgical Research

Kylie J. Walters

National Cancer Institute at Frederick - Structural Biophysics Laboratory

Mark R. Gilbert

Government of the United States of America - Neuro-Oncology Branch

Mioara Larion

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

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Abstract

Targeting glutamine metabolism in cancer has become 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). Here, we report the adaptability of IDH1mut 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 IDH1mut 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 IDH1mut gliomas.

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

Suggested Citation

Ruiz-Rodado, Victor and Lita, Adrian and Dowdy, Tyrone and Celiku, Orieta and Cavazos-Saldana, Alejandra and Wang, Herui and Li, Aiguo and Zhang, Wei and Song, Hua and Zhang, Meili and Ahn, Susie and Davis, Dionne and Chen, Xiang and Zhuang, Zhengping and Herold-Mende, Christel and Walters, Kylie J. and Gilbert, Mark R. and Larion, Mioara, Metabolic Plasticity of IDH1- Mutant Glioma Cell Lines Is Responsible for Low Sensitivity to Glutaminase Inhibition (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3387658 or http://dx.doi.org/10.2139/ssrn.3387658
This version of the paper has not been formally peer reviewed.

Victor Ruiz-Rodado

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Adrian Lita

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Tyrone Dowdy

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Orieta Celiku

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Alejandra Cavazos-Saldana

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Herui Wang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Aiguo Li

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Wei Zhang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Bethesda, MD
United States

Hua Song

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Bethesda, MD
United States

Meili Zhang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Bethesda, MD
United States

Susie Ahn

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch

Bethesda, MD
United States

Dionne Davis

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

Xiang Chen

National Cancer Institute at Frederick, Center for Cancer Research, Structural Biophysics Laboratory

Frederick, MD
United States

Zhengping Zhuang

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS), Surgical Neurology Branch ( email )

Bethesda, MD
United States

Christel Herold-Mende

Heidelberg University - Division of Neurosurgical Research

Heidelberg
Germany

Kylie J. Walters

National Cancer Institute at Frederick - Structural Biophysics Laboratory ( email )

Frederick, MD
United States

Mark R. Gilbert

Government of the United States of America - Neuro-Oncology Branch

Bethesda, MD
United States

Mioara Larion (Contact Author)

National Institutes of Health (NIH), National Cancer Institute, Neuro-Oncology Branch ( email )

Bethesda, MD
United States

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