Mutational Pathway Determines Whether Drug Gradients Accelerate Evolution of Drug-Resistant Cells
Mutational Pathway Determines Whether Drug Gradients Accelerate Evolution of Drug-Resistant Cells
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DOI：
10.1103/physrevlett.109.088101
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发表时间：
2012-08-20
影响因子：
8.6
通讯作者：
Allen, Rosalind J.
中科院分区：
文献类型：
--
作者：
Greulich, Philip;Waclaw, Bartlomiej;Allen, Rosalind J.
药物梯度被认为在细菌对抗生素的耐药性和肿瘤对抗癌药物的耐药性的进化中起重要作用。我们使用统计物理模型来研究暴露于药物梯度的恶性细胞群体的演变，其中通过涉及多个突变的突变途径出现耐药性。我们表明，当突变途径涉及一长串耐药性不断增加的突变体时，不均匀的药物分布有可能加速耐药性的出现，但如果该途径较短或穿过适合度谷，则耐药性的进化实际上可能会减慢药物梯度。这些预测可以通过实验得到验证，并可能有助于改善对抗耐药性出现的策略。
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.