RT Journal Article SR Electronic T1 Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells JF Science JO Science FD American Association for the Advancement of Science SP 1555 OP 1559 DO 10.1126/science.1174229 VO 325 IS 5947 A1 Yun, Jihye A1 Rago, Carlo A1 Cheong, Ian A1 Pagliarini, Ray A1 Angenendt, Philipp A1 Rajagopalan, Harith A1 Schmidt, Kerstin A1 Willson, James K. V. A1 Markowitz, Sandy A1 Zhou, Shibin A1 Diaz, Luis A. A1 Velculescu, Victor E. A1 Lengauer, Christoph A1 Kinzler, Kenneth W. A1 Vogelstein, Bert A1 Papadopoulos, Nickolas YR 2009 UL http://science.sciencemag.org/content/325/5947/1555.abstract AB Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently up-regulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wild-type KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Together, these data suggest that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.