Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 4, Pages 1591-1602Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78239
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Funding
- KAKENHI [24791501, 25462258, 24592126, 25293309]
- Ludwig Institute for Cancer Research from the National Institute for Neurological Diseases and Stroke [NS73831]
- National Cancer Institute [CA151819]
- Takeda Science Foundation
- Ben and Catherine Ivy Foundation
- Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society
- Grants-in-Aid for Scientific Research [25670535, 24592126, 25293309, 24791501, 15K09996, 26830073, 25293265, 26462158, 25462258] Funding Source: KAKEN
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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 alpha-ketoglutarate-dependent (alpha KG-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.
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