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Science 325 (5947): 1555-1559

Copyright © 2009 by the American Association for the Advancement of Science

Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells

Jihye Yun,1 Carlo Rago,1 Ian Cheong,1 Ray Pagliarini,1,* Philipp Angenendt,1 Harith Rajagopalan,1,{dagger} Kerstin Schmidt,1 James K. V. Willson,2 Sandy Markowitz,3 Shibin Zhou,1 Luis A. Diaz, Jr,1 Victor E. Velculescu,1 Christoph Lengauer,1,{ddagger} Kenneth W. Kinzler,1 Bert Vogelstein,1,§ Nickolas Papadopoulos1

Abstract: 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.

1 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
2 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Department of Medicine and Ireland Cancer Center, Case Western Reserve University and Case Medical Center of University Hospitals of Cleveland and Howard Hughes Medical Institute, Cleveland, OH 44106, USA.

* Present address: Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

{dagger} Present address: Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

{ddagger} Present address: Sanofi-Aventis, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.

§ To whom correspondence should be addressed. E-mail: vogelbe{at}jhmi.edu

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