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Nature genetics DOI:10.1038/ng.2471

MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors.

Publication TypeJournal Article
Year of Publication2013
AuthorsBirsoy, K, Wang, T, Possemato, R, Yilmaz, OH, Koch, CE, Chen, WW, Hutchins, AW, Gultekin, Y, Peterson, TR, Carette, JE, Brummelkamp, TR, Clish, CB, Sabatini, DM
JournalNature genetics
Date Published2013/01/01

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.