Chromosomal instability is seen in most tumours, and makes them a genetic moving target for therapy. We have been using this trait as a therapeutic target, as it is rare in normal dividing cells. We have found a stereotypic metabolic response to chromosomal instabilty that makes cells vulnerable to relatively mild disruptions of glycolysis. Using genetic screening in Drosophila we have found several metabolic gene knockdowns that are able to induce cell death in CIN cells and block the growth of CIN tumours in vivo.
Recently we have carried out proteomic and metabolomic analyses of cells with induced chromosomal instability and are now testing the hypothesis that glyceroneogenesis is a key regulator of cytoplasmic NADH that affects mitochondrial ROS generation through the glycerol phosphate shuttle. Because tumours with chromosomal instability are already redox stressed, we find that they are unable to tolerate mild increases in ROS, such as those generated by PEPCK depletion. We will present our data on the effects of inhibiting glyceroneogenesis or the glycerol phosphate shuttle on the growth of CIN tumour explants and discuss the merits of therapeutic approaches that couple ROS generation to glycolytic flux.