Abstract
There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anticancer therapy are under way. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Furthermore, forced MCT1 expression in 3-BrPA–resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.
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Acknowledgements
We thank members of the Sabatini laboratory and F. Reinhardt for advice and assistance. This work was supported by grants from the US National Institutes of Health (NIH; CA103866) and the David H. Koch Institute for Integrative Cancer Research to D.M.S. and fellowships from the Jane Coffin Childs Memorial Fund to K.B. and US National Science Foundation to T.W. D.M.S. is an investigator of the Howard Hughes Medical Institute.
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K.B. and D.M.S. conceived the project. K.B. designed and performed most experiments and data analyses, with input from D.M.S. T.W. assisted with initial experiments and data analysis. C.E.K., O.H.Y., R.P., W.W.C., Y.G. and A.W.H. assisted with experiments, and T.R.P., J.E.C. and T.R.B. assisted with haploid genetic screening. C.B.C. performed metabolite profiling and analysis. K.B. and D.M.S. wrote and edited the manuscript.
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Birsoy, K., Wang, T., Possemato, R. et al. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat Genet 45, 104–108 (2013). https://doi.org/10.1038/ng.2471
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DOI: https://doi.org/10.1038/ng.2471
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