Optimal chemotherapy counteracts cancer adaptive resistance in a cell-based, spatially-extended, evolutionary model

Abstract

Abstract Most aggressive cancers are incurable due to their fast evolution of drug resistance. We model cancer growth and adaptive response in a simplified cell-based (CB) setting, assuming a genetic resistance to two chemotherapeutic drugs. We show that optimal administration protocols can steer cells resistance and turned it into a weakness for the disease. Our work extends the population-based model proposed by Orlando et al (2012 Phys. Biol.), in which a homogeneous population of cancer cells evolves according to a fitness landscape. The landscape models three types of trade-offs, differing on whether the cells are more, less, or equal effective when generalizing resistance to two drugs as opposed to specializing to a single one. The CB framework allows us to include genetic heterogeneity, spatial competition, and drugs diffusion, as well as realistic administration protocols. By calibrating our model on Orlando et al’s assumptions, we show that dynamical protocols that alternate the two drugs minimize the cancer size at the end of (or at mid-points during) treatment. These results significantly differ from those obtained with the homogeneous model—suggesting static protocols under the pro-generalizing and neutral allocation trade-offs—highlighting the important role of spatial and genetic heterogeneities. Our work is the first attempt to search for optimal treatments in a CB setting, a step forward toward realistic clinical applications.