title: Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment.
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.
authors: Kazuhiro
authors: K
authors: Tanaka
authors: Takashi
authors: T
authors: Sasayama
authors: Yasuhiro
authors: Y
authors: Irino
authors: Kumi
authors: K
authors: Takata
authors: Hiroaki
authors: H
authors: Nagashima
authors: Naoko
authors: N
authors: Satoh
authors: Katsusuke
authors: K
authors: Kyotani
authors: Takashi
authors: T
authors: Mizowaki
authors: Taichiro
authors: T
authors: Imahori
authors: Yasuo
authors: Y
authors: Ejima
authors: Kenta
authors: K
authors: Masui
authors: Beatrice
authors: B
authors: Gini
authors: Huijun
authors: H
authors: Yang
authors: Kohkichi
authors: K
authors: Hosoda
authors: Ryohei
authors: R
authors: Sasaki
authors: Paul S
authors: PS
authors: Mischel
authors: Eiji
authors: E
authors: Kohmura
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D053119:Benzophenanthridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D004734:Energy Metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007656:Ketoglutaric Acids / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013702:Temporal Lobe / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D053119:Benzophenanthridines; D007211:Indoles; D007656:Ketoglutaric Acids; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; C000598981:compound 968; D005973:Glutamine; D018698:Glutamic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005972:Glutaminase; C572919:PP242