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

TL;DR

This study uses a statistical physics model to explore how drug gradients influence the evolution of resistance in cells, revealing that gradient effects depend on the mutational pathway length and complexity.

Contribution

It demonstrates that drug gradients can either accelerate or slow resistance evolution depending on the mutational pathway characteristics.

Findings

Gradients accelerate resistance with long mutational pathways.

Gradients may slow resistance if pathways are short or involve fitness valleys.

Predictions can be experimentally tested to improve resistance management strategies.

Abstract

Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anti-cancer 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 non-uniform 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 combatting the emergence of resistance.