Mutant KRAS Copy-Number Gain Drives Metabolic Reprogramming

Activating mutations in one Kras allele are sufficient to induce lung tumorigenesis in mice, but high-grade murine tumors often display relative gain of mutant Kras through loss of wild-type Kras and/or increased mutant Kras copy number, suggesting that there is selective pressure for increased mutant Kras activity. Kerr and colleagues used Trp53-null murine embryonic fibroblasts harboring heterozygous or homozygous Kras mutations to investigate the mechanism by which Kras copy-number gains contribute to tumor progression and showed that although no obvious change in early passage proliferation kinetics was observed, cells with homozygous Kras mutations displayed upregulated glycolytic gene expression and increased glucose uptake, lactate secretion, and glycolytic capacity compared to cells with heterozygous Kras mutation. The enhanced glycolytic activity in homozygous Kras-mutant cells was accompanied by an increase in glucose-derived tricarboxylic acid (TCA) metabolites, as well as glutathione and its precursors, suggesting metabolic rewiring toward increased glutathione biosynthesis. In line with these findings, homozygous Kras-mutant cells were characterized by increased antioxidant gene expression, higher NADPH/NADP⁺ and GSH/GSSG ratios, reduced reactive oxygen species (ROS), and increased resistance to ROS inducers. Notably, homozygous Kras mutant cells were more sensitive to glucose deprivation or inhibition of glycolysis than heterozygous cells, and combined depletion of glucose and GSH was shown to enhance apoptosis. Analysis of a heterozygous Kras-mutant tumor mouse model known to undergo mutant allele enrichment during tumor progression showed that late tumors were also characterized by a metabolic shift toward glucose-derived TCA metabolites and glutathione, and showed enhanced sensitivity to combined inhibition of glycolysis and GSH biosynthesis. Consistent with these mouse data, analysis of human lung tumor gene copy-number and gene expression data confirmed that KRAS mutation and copy-number gain correlated with upregulation of glycolytic- and glutathione-related gene expression. Together, these data suggest that KRAS-mutant tumors are not metabolically equivalent and may have distinct therapeutic vulnerabilities.

Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 2016;531:110–3.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.