Mathematical modeling of drug resistance in heterogeneous cancer cell populations

Abstract

Drug resistance is one of the most intractable issues associated with cancer treatment in clinical practice. Mathematical models provide an analytic framework for facilitating the understanding of resistance evolution dynamics and the design of cancer clinical trial. In this paper, we develop an elementary, compartmental mathematical model for absolute drug resistance, focusing on the effects of point mutations in genetic drivers of malignancy. A set of ordinary differential equations (ODEs) is used to describe the dynamics of competing heterogeneous cancer cell populations while taking account of pharmacokinetics. All possible equilibria and their local geometric properties are analyzed, with the result suggests that the system exhibits bistable dynamics. The existence of optimal treatment time is discussed. To identify the critical parameters which influence cellular dynamics, we also perform parameter sensitivity analysis. Finally, numerical simulations are presented to verify the feasibilities of our analytical results and to find that the pre-existence of resistant cell phenotypes contributes more than resistant mutants generated during the treatment phase.