Invited Talk: Engineered Drug Resistance Implicates Non-Genetic Mechanisms as Potential Drivers of Rapid Clonal Expansion

Drug resistance complicates the treatment of infectious disease and cancer and often arises by increased expression of genes that neutralize or reduce the activity of the drug. To investigate this and other expression-based mechanisms in living cells, we use synthetic gene networks to control a homologue of the cancer-related human multidrug resistance gene MDR1in the eukaryotic model organism Saccharomyces cerevisiae. Using this system, we explore how different network features, or motifs, contribute to cell survival in the presence of a cytotoxic drug. We show that the coherent feedforward motif can enhance cell survival in the presence of the drug by allowing rapid and prolonged activation of gene expression, and that combining coherent feedforward and positive feedback motifs leads to increased drug resistance. Our results provide direct evidence that certain gene network motifs cause reduced susceptibility to drug treatment, and confirm theoretical predictions about the potential importance of gene network structure in the development of drug resistance in the absence of acquired mutations.