Modeling continuous levels of resistance to multidrug therapy in cancer

Abstract

Multidrug resistance consists of a series of genetic and epigenetic alternations that involve multifactorial and complex processes, which are a challenge to successful cancer treatments. Accompanied by advances in biotechnology and high-dimensional data analysis techniques that are bringing in new opportunities in modeling biological systems with continuous phenotypic structured models, we investigate multidrug resistance by studying a cancer cell population model that considers a multi-dimensional continuous resistance trait to multiple drugs. We compare our continuous resistance trait model with classical models that assume a discrete resistance state and classify the cases when the continuum and discrete models yield different dynamical patterns in the emerging heterogeneity in response to drugs. We also compute the maximal fitness resistance trait for various continuum models and study the effect of epimutations. Finally, we demonstrate how our approach can be used to study tumor growth with respect to the turnover rate and the proliferating fraction. We show that a continuous resistance level model may result in different dynamics compared with the predictions of other discrete models.