Inhibition of Glutamine Metabolism Sensitizes Cancer to Further Pharmacological Disruption and Yields Clinically Viable Treatment Options
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Poore, Bradley A
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Many cancers are dependent on glutamine and will die or senesce in the absence of glutamine. This phenomenon is knows as, “glutamine addiction.” This work demonstrates that disrupting glutamine metabolism, through glutaminase or mTORC1 inhibition, is a potent therapeutic modality in multiple cancer types and further sensitizes cells to traditional chemotherapeutic agents. Cancers over-expressing KRAS, such as pancreatic cancer, are frequently addicted to glutamine. Treatment with BPTES, a glutaminase inhibitor, still allowed KRAS-driven pancreatic tumors to grow, despite decreased glutamine utilization. Metabolic analysis revealed that cancer cells upregulated glycolysis and glycogenesis after prolonged treatment with BPTES. We hypothesized that glycogenesis inhibition would enhance the efficacy of BPTES. The combination of BPTES and metformin, a glucose metabolism-disrupting drug used to treat Type II diabetes, decreased tumor burden significantly better than either agent alone. In multiple pediatric low-grade glioma models, which similarly have activation of the RAS/MAP kinase pathway, response to treatment with the mTORC1 inhibitor everolimus varied, despite metabolic studies showing that everolimus decreased the incorporation of glutamine into glutamate and glutathione. Cells use glutathione for detoxification of a variety of compounds, including commonly used chemotherapies. We hypothesized everolimus would sensitize PLGG to carboplatin treatment, which glutathione is typically able to detoxify. The combination of everolimus and carboplatin was synergistic and decreased tumor growth better than either agent alone. We demonstrate that inhibition of glutamine metabolism sensitizes cancer cells to further pharmacological perturbation, suggesting that patients with glutamine-dependent cancers could benefit from glutamine metabolic inhibitors as part of their treatment regimen.