Abstract: Drug resistance is one of the most intractable issues in targeted therapy for cancer diseases. It has also been demonstrated to be related to cancer heterogeneity, which promotes the emergence of treatment-refractory cancer cell populations. Focusing on how cancer cells develop resistance during the encounter with targeted drugs and the immune system, we propose a mathematical model for studying the dynamics of drug resistance in a conjoint heterogeneous tumor-immune setting. We analyze the local geometric properties of the equilibria of the model. Numerical simulations show that the selectively targeted removal of sensitive cancer cells may cause the initially heterogeneous population to become a more resistant population. Moreover, the decline of immune recruitment is a stronger determinant of cancer escape from immune surveillance or targeted therapy than the decay in immune predation strength. Sensitivity analysis of model parameters provides insight into the roles of the immune system combined with targeted therapy in determining treatment outcomes.

Key words: mathematical model, drug resistance, cancer heterogeneity, immune system, targeted therapy