Abstract
The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate-dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Benzophenanthridines / administration & dosage
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Benzophenanthridines / pharmacology
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Benzophenanthridines / therapeutic use*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Citric Acid Cycle
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Drug Resistance, Neoplasm / physiology*
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Drug Synergism
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Energy Metabolism
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Gas Chromatography-Mass Spectrometry
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Glioblastoma / drug therapy*
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glutamic Acid / metabolism
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Glutaminase / antagonists & inhibitors
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Glutaminase / biosynthesis
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Glutaminase / genetics
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Glutaminase / physiology*
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Glutamine / metabolism*
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Glycolysis
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology*
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Indoles / therapeutic use
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Ketoglutaric Acids / metabolism
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Magnetic Resonance Spectroscopy
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Male
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Metabolome / drug effects
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Targeted Therapy*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Purines / administration & dosage
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Purines / pharmacology*
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Purines / therapeutic use
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RNA, Small Interfering / pharmacology
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Rotarod Performance Test
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Signal Transduction / drug effects
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Signal Transduction / physiology
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Temporal Lobe / metabolism
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Xenograft Model Antitumor Assays
Substances
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Benzophenanthridines
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Indoles
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Ketoglutaric Acids
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Purines
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RNA, Small Interfering
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compound 968
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Glutamine
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Glutamic Acid
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MTOR protein, human
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TOR Serine-Threonine Kinases
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Glutaminase
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PP242