title: Mutational pathway determines whether drug gradients accelerate evolution of drug-resistant cells.
abstract: Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anticancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a nonuniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combating the emergence of resistance.
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Greulich
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Waclaw
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Allen
mesh_terms: D002468:Cell Physiological Phenomena / Q000187:drug effects* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D010599:Pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations