mTORC1 Signaling Allows Cancer Cells to Escape Glycolytic Dependency

Glycolysis is elevated in many tumors despite the presence of oxygen; however, glycolysis inhibitors, including the glucose analog 2-deoxy-D-glucose (2DG), have not been successful in clinical trials. Pusapati and colleagues hypothesized that tumors might escape glycolytic dependence via utilization of other metabolites or metabolic pathways. To begin to model the escape from glycolysis dependency, a panel of cancer cell lines were treated with 2DG and classified as glycolysis-dependent or glycolysis-independent based on the response. The glycolysis-independent cells exhibited increased oxidative phosphorylation, which was promoted by glutamine. Consistent with these findings, glutamine could rescue the growth of glycolysis-independent cells, but not glycolysis-dependent cells, under glycolytic stress. In glycolysis-independent cells, treatment with 2DG drove glucose carbons through the pentose phosphate pathway and back into glycolysis, allowing glucose to continue to contribute metabolic precursors to the TCA cycle when glycolysis is disrupted. Treatment with 2DG reduced mTORC1 signaling in glycolysis-dependent but not glycolysis-independent cells, suggesting that sustained mTORC1 signaling contributes to glycolytic independence. Indeed, activation of mTORC1 in glycolysis-dependent cells rescued them from 2DG toxicity, and treatment of glycolysis-independent cell xenografts with 2DG and everolimus, a clinical mTORC1 inhibitor, reduced tumor burden. In an orthogonal approach to inhibit glycolysis in vivo, glucose-6-phosphate isomerase (GPI), the enzyme inhibited by 2DG, was inducibly knocked down to mimic 2DG treatment. GPI silencing initially inhibited tumor growth, but tumors eventually became glycolysis-independent. However, everolimus inhibited glycolysis-independent tumor growth, further supporting the importance of mTORC1 in promoting glycolysis independence in vivo. Altogether, these findings indicate that mTORC1 signaling drives metabolic rewiring to allow tumor cells to become glycolysis independent, suggesting that mTORC1 pathway inhibition may enhance the efficacy of glycolysis inhibitors.

Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, et al. mTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell 2016 Mar 24 [Epub ahead of print].

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