Introduction: RCC has been recognized in recent years as a uniquely metabolic disease. All histologic types of RCC exhibit increase in aerobic glycolysis with disease progression. The TCGA-RCC study showed that high grade, high stage, and low survival are associated with a shift to aerobic glycolysis and a decrease in oxidative phosphorylation. Approaches targeting glucose metabolism in RCC such as GLUT1 inhibitors, hexokinase inhibitors, GAPDH inhibitor, and PKM2 inhibitor showed limited clinical benefit. Monocarboxylate transporters (MCTs) play a major role in the export/import of the glycolytic end-product lactate. Different MCT isoforms are differentially expressed in RCC tissues with an increase in the expression of MCT1 and MCT4 in clear-cell RCC and papillary RCC. Here we hypothesized that MCT inhibition may be an attractive therapeutic strategy against RCC cells.
Methods: We analyzed the expression levels of MCTs in RCC tissues using public datasets from Oncomine. We treated normal renal epithelial and renal cell carcinoma cells with varying concentrations of MCT inhibitors AR-C155858, AZD3965, or syrosingopine either singly or in combination with sunitinib or everolimus and assessed cell survival, cell viability, proliferation, clonogenic ability, survival in 3-D models, and glycolytic activity. We treated xenografts of ccRCC cells in mice with MCT inhibitors, sunitinib, or everolimus singly or in combination and assessed tumor growth.
Results: We found that the suppression of MCT activity using the MCT antagonists AR-C155858, AZD3965, or syrosingopine not only diminished the proliferation, survival, and clonogenic ability of RCC cells, but also potentiated the response of RCC cells to treatment with sunitinib or everolimus. MCT inhibitors inhibited the metabolic adaptation of ccRCC cells when treated with sunitinib or everolimus. Tumor growth of ccRCC xenografts was suppressed significantly when treated with a combination of MCT inhibitors with sunitinib or everolimus. These findings imply that MCT inhibition may be an effective strategy to develop combinatorial therapies in renal cell carcinoma.
Conclusions: MCT inhibition may improve the anti-tumor effects of tyrosine kinase or mTOR inhibitors in renal cell carcinoma.
Source of Funding: DoD-PCRP PC190332 (W81XWH2010794), University of Toledo College of Medicine and Life Sciences, NIH/NCI 1R21CA202404, NIH/NCI 1R03CA198696
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