Targeting of oncogenes can produce tumor shrinkage, but the frequency of relapse indicates that a population of tumor cells survives oncogene inhibition. In a study in a KRAS-mutant pancreatic ductal adenocarcinoma mouse model reported in Nature, Viale and colleagues found that a subpopulation of dormant tumor cells that survived oncogene ablation and were responsible for tumor relapse had features of cancer stem cells and relied on oxidative phosphorylation for survival.
Transcriptomic and metabolic analyses of these surviving cells showed pronounced expression of genes regulating mitochondrial function, autophagy, and lysosome activity, with increased reliance on mitochondrial respiration and reduced dependence on glycolysis in cellular energy use being observed. The surviving cells were sensitive to oxidative phosphorylation inhibitors, which were found to inhibit tumor recurrence.
The investigators concluded: “Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.” ■
Viale A, et al: Nature 514:628-632, 2014.