Dramatic progress has been made in recent years developing therapeutics that specifically target signaling pathways activated by genetic alterations in cancer. While such drugs have elicited promising clinical responses, the majority of patients eventually cease to respond to treatment.
Understanding the causes of drug resistance has the potential to nominate new therapeutic strategies and guide the development of new drugs to achieve greater and more sustained responses. Using cell-based models of drug-response, we can use genome-scale RNA interference screens to systematically identify loss-of-function events that either promote resistance or induce sensitivity to a particular drug.
This approach enables the unbiased discovery of candidate resistance effectors that may be targeted in combination with established treatments, or suggest new targets for novel drug discovery efforts. We can also culture cancer cell lines in the presence of drugs and generate ‘isogenic’ pairs of cell lines, the parental sensitive line and the daughter resistant lines. By comparing the differences between these pairs of lines at the genetic and biochemical level, we can identify the alterations that drive drug resistance.
These data may then be integrated with candidate clinical resistance genes identified in drug-resistant tumours from cancer patients. Overall, this program of investigation should further our understanding of key survival pathways and mechanisms of drug resistance and accelerate the rational deployment of combination therapies.