Mutational pathway determines whether drug gradients accelerate evolution of drug-resistant cells

Mutational pathway determines whether drug gradients accelerate evolution of drug-resistant cells

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...

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Veröffentlicht in:Physical review letters 2012-08, Vol.109 (8), p.088101-088101, Article 088101
Hauptverfasser: Greulich, Philip, Waclaw, Bartłomiej, Allen, Rosalind J
Format: Artikel
Sprache:eng
Schlagworte:
Cell Physiological Phenomena - drug effects
Cell Physiological Phenomena - genetics
Dose-Response Relationship, Drug
Drug Resistance - genetics
Models, Genetic
Mutation
Pharmaceutical Preparations - administration & dosage
Pharmacokinetics
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creator Greulich, Philip
Waclaw, Bartłomiej
Allen, Rosalind J
description 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.
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subjects Cell Physiological Phenomena - drug effects
Cell Physiological Phenomena - genetics
Dose-Response Relationship, Drug
Drug Resistance - genetics
Models, Genetic
Mutation
Pharmaceutical Preparations - administration & dosage
Pharmacokinetics
title Mutational pathway determines whether drug gradients accelerate evolution of drug-resistant cells
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