Dabi, A. | Search bioRxiv

bioRxiv2024

Evolutionary rescue model informs strategies for driving cancer cell populations to extinction

Cancers exhibit a remarkable ability to develop resistance to a range of treatments, often resulting in relapse following first-line therapies and significantly worse outcomes for subsequent treatments. While our understanding of the mechanisms and dynamics of the emergence of resistance during cancer therapy continues to advance, questions remain about how to minimize the probability that resistance will evolve, thereby improving long-term patient outcomes. Here, we present an evolutionary simulation model of a clonal population of cells that can acquire resistance mutations to one or more treatments. We leverage this model to examine the efficacy of a two-strike "extinction therapy" protocol, in which two treatments are applied sequentially to first contract the population to a vulnerable state and then push it to extinction, and compare it to a combination therapy protocol. We investigate how factors such as the timing of the switch between the two strikes, the rate of emergence of resistant mutations, the doses of the applied drugs, the presence of cross-resistance, and whether resistance is a binary or a quantitative trait affect the outcome. Our results show that the timing of switching to the second strike has a marked effect on the likelihood of driving the cancer to extinction, and that extinction therapy outperforms combination therapy when cross-resistance is present. We conduct an in silico trial that reveals when and why a second strike will succeed or fail. Finally, we demonstrate that our conclusions hold whether we model resistance as a binary trait or as a quantitative, multi-locus trait.

evolutionary biology↗

bioRxiv2024

Population size rescaling significantly biases outcomes of forward-in-time population genetic simulations

Simulations are an essential tool in all areas of population genetic research, used in tasks such as the validation of theoretical analysis and the study of complex evolutionary models. Forward-in-time simulations are especially flexible, allowing for various types of natural selection, complex genetic architectures, and non-Wright-Fisher dynamics. However, their intense computational requirements can be prohibitive to simulating large populations and genomes. A popular method to alleviate this burden is to scale down the population size by some scaling factor while scaling up the mutation rate, selection coefficients, and recombination rate by the same factor. However, this rescaling approach may in some cases bias simulation results. To investigate the manner and degree to which rescaling impacts simulation outcomes, we carried out simulations with different demographic histories and distributions of fitness effects using several values of the rescaling factor, Q, and compared the deviation of key outcomes (fixation times, allele frequencies, linkage disequilibrium, and the fraction of mutations that fix during the simulation) between the scaled and unscaled simulations. Our results indicate that scaling introduces substantial biases to each of these measured outcomes, even at small values of Q. Moreover, the nature of these effects depends on the evolutionary model and scaling factor being examined. While increasing the scaling factor tends to increase the observed biases, this relationship is not always straightforward, thus it may be difficult to know the impact of scaling on simulation outcomes a priori. However, it appears that for most models, only a small number of replicates was needed to accurately quantify the bias produced by rescaling for a given Q. In summary, while rescaling forward-in-time simulations may be necessary in many cases, researchers should be aware of the rescaling procedures impact on simulation outcomes and consider investigating its magnitude in smaller scale simulations of the desired model(s) before selecting an appropriate value of Q. ARTICLE SUMMARYComputer simulations are an indispensable tool for researchers studying the dynamics of population genetic models, but often require large computing resources and long run times. A widely used approximation alleviates these computational requirements by simulating a smaller population and increasing the values of other model parameters to compensate. However, this results in significant biases for important simulation outcomes. Fortunately, the direction and magnitude of these biases can be measured beforehand by carrying out a relatively small number of simulations.

evolutionary biology↗