Glucose Deprivation Contributes to the Development of <i>KRAS</i> Pathway Mutations in Tumor Cells

TLDR

Mutations in oncogenes and tumor suppressor genes that affect glucose metabolism enable cancer cells to outgrow neighboring healthy cells. The study aims to identify microenvironmental conditions that confer a selective growth advantage to cancer cells. Low glucose availability promotes acquisition of KRAS mutations, with mutant cells overexpressing GLUT1 and surviving better, while wild‑type cells in low glucose largely die but survivors upregulate GLUT1 and occasionally acquire KRAS mutations, indicating glucose deprivation drives growth‑promoting oncogenic mutations. Yun et al.

Abstract

Desperately Seeking Glucose Mutations in oncogenes and tumor suppressor genes allow cancer cells to outgrow their neighboring healthy cells. What microenvironmental conditions provide a selective growth advantage to these cells? Yun et al. (p. 1555 , published online 6 August) identify low glucose availability as a microenvironmental factor driving the acquisition of KRAS oncogenic mutations that allow cancer cells to survive and grow. In genetically matched colorectal cancer cells that differed only in the mutational status of the KRAS oncogene, mutant cells selectively overexpressed glucose transporter-1 and exhibited enhanced glucose uptake and glycolysis. When cells with wild-type KRAS were placed in a low-glucose environment, very few cells survived but most of the survivors expressed high levels of glucose transporter-1, and a small percentage of the survivors had acquired new KRAS mutations. Thus, glucose deprivation may help to drive the acquisition of cell growth–promoting oncogenic mutations during tumor development.