Targeting chromosomal instability

Z Shaukat1, D Liu1, R Hussain1, M Khan1, S Basnet1, R Saint2 and S Gregory1

  1. School of Biological Sciences, University of Adelaide, Adelaide, Australia
  2. Flinders University, Adelaide, Australia

Chromosomal INstability (CIN), a hallmark of cancer, refers to cells with an increased rate of gain or loss of whole chromosomes or chromosome parts. As CIN is not found in normal cells, it offers a cancer-specific target for therapy. We generated a CIN model in Drosophila by knocking down the spindle checkpoint, and screened for candidate knockdowns that induce apoptosis only in CIN cells. Genes identified include those involved in the DNA damage/repair pathway, JNK signaling pathway, mitotic cytoskeletal regulation and metabolism. The screen demonstrates that it is feasible to selectively kill cells with CIN. CIN is linked to the progression of tumors with poor clinical outcomes such as drug resistance. CIN can give tumors the diversity to resist therapy, but it comes at the cost of significant stress to tumor cells. To tolerate this, cancer cells must modify their energy use to provide adaptation against genetic changes as well as to promote their survival and growth. We have demonstrated that CIN induction causes sensitivity to metabolic stress, with disrupted glycolytic flux and mitochondrial membrane potential. We showed that mild metabolic disruption that does not affect normal cells, can lead to high levels of oxidative stress and subsequent cell death in CIN cells because they are already managing elevated stress levels. We will present our latest work testing the effect of metabolic intervention in a tumour explant model. Altered metabolism is a differential characteristic of cancer cells, so our identification of key regulators that can exploit these changes to cause cell death may provide tumour-specific drug targets, especially for advanced cancers that exhibit CIN.