Diverse mutant selection windows shape spatial heterogeneity in evolving populations.

Abstract

Mutant selection windows (MSWs), the range of drug concentrations that select for drug-resistant mutants, have long been used as a model for predicting drug resistance and designing optimal dosing strategies in infectious disease. The canonical MSW model offers comparisons between two subtypes at a time: drug-sensitive and drug-resistant. In contrast, the fitness landscape model with N alleles, which maps genotype to fitness, allows comparisons between N genotypes simultaneously, but does not encode continuous drug response data. In clinical settings, there may be a wide range of drug concentrations selecting for a variety of genotypes in both cancer and infectious diseases. Therefore, there is a need for a more robust model of the pathogen response to therapy to predict resistance and design new therapeutic approaches. Fitness seascapes, which model genotype-by-environment interactions, permit multiple MSW comparisons simultaneously by encoding genotype-specific dose-response data. By comparing dose-response curves, one can visualize the range of drug concentrations where one genotype is selected over another. In this work, we show how N-allele fitness seascapes allow for N * 2N-1 unique MSW comparisons. In spatial drug diffusion models, we demonstrate how fitness seascapes reveal spatially heterogeneous MSWs, extending the MSW model to more fully reflect the selection of drug resistant genotypes. Furthermore, using synthetic data and empirical dose-response data in cancer, we find that the spatial structure of MSWs shapes the evolution of drug resistance in an agent-based model. By simulating a tumor treated with cyclic drug therapy, we find that mutant selection windows introduced by drug diffusion promote the proliferation of drug resistant cells. Our work highlights the importance and utility of considering dose-dependent fitness seascapes in evolutionary medicine.