Development of a Theoretical Framework to Understand Drug-Induced Persistence in Cancer

Despite progress in cancer biology and drug development, suboptimal treatment response remains a major clinical challenge. In particular, persistence, a reversible drug-tolerant state obtained via phenotypic shifts distinct from resistance, has garnered increasing attention in oncology. Drug-tolerant persisters (DTPs) are typically marked by quiescence, though some can regain the ability to proliferate and transition into cycling persisters. Their prolonged exposure to cytotoxic agents can ultimately lead to mutants with true resistance. In this work, we introduce a general phenomenological framework that describes how phenotypic plasticity gives rise to persistence. The framework builds on recent experimental observations of intra- and inter-clonal heterogeneity and the possible role of the drug itself in facilitating the adaptation for survival. Our theoretical approach, using a partial differential equation with two continuous variables to represent cell states, predicts both an optimal drug concentration and effective drug holiday schedules that may limit persister formation. These findings align with recent experimental evidence for phenotypic transitions along a “resistance continuum” and offer insights for improving cancer therapy. Furthermore, the model can be generalized to investigate other related phenomena, including tumor dormancy and recurrence.