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

K Birsoy, T Wang, R Possemato, OH Yilmaz, CE Koch… - Nature …, 2013 - nature.com
Nature genetics, 2013nature.com
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 …
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.
nature.com