Understanding therapeutic tolerance through a mathematical model of drug-induced resistance

Abstract

There is growing recognition that phenotypic plasticity enables cancer cells to adapt to various environmental conditions. An example of this adaptability is the persistence of an initially sensitive population of cancer cells in the presence of therapeutic agents. Understanding the implications of this druginduced resistance is essential for predicting transient and long-term tumor tumor dynamics subject to treatment. This paper introduces a mathematical model of this phenomenon of drug-induced resistance which provides excellent fits to time-resolved in vitro experimental data. From observational data of total numbers of cells, the model unravels the relative proportions of sensitive and resistance subpopulations, and quantifies their dynamics as a function of drug dose. The predictions are then validated using data on drug doses which were not used when fitting parameters. The model is then used, in conjunction with optimal control techniques, in order to discover dosing strategies that might lead to better outcomes as quantified by lower total cell volume.