A Mathematical Model of Persister Cell Plasticity and Its Impact on Adaptive Cancer Therapy

The emergence of resistance to therapy remains a significant obstacle to successful treatment in cancer that is driven by somatic evolution. Adaptive therapies represent a novel approach to manage the emergence of resistance, by leveraging the competition between different cell phenotypes to control tumor burden rather than aiming for complete eradication. However, the emergence of phenotypically plastic persister cells, exhibiting transient epigenetic resistance, poses a significant challenge to the efficacy of these approaches, and their specific impact is often overlooked in preclinical and mathematical models. This study investigates the role of persisters within adaptive therapy using a spatial agent-based model simulating sensitive, persistent, and genetically resistant cell populations. Our simulations reveal that persisters critically undermine treatment efficacy, significantly reducing progression-free survival (PFS) by approximately 40% (average 207 vs. 344 days in simulations) as they provide a reservoir for acquiring genetic resistance. Furthermore, tumors with higher levels of epigenetic resistance (more robust persisters) showed accelerated evolution towards resistance dominance phenotypes. The model showed treatment was most effective when sensitive cells initially dominated the tumor microenvironment. These findings highlight that persister dynamics are crucial determinants of adaptive therapy outcomes, suggesting that future strategies must account for epigenetic resistance, potentially informing approaches to assess tumor composition and sensitivity to better tailor treatments and improve patient outcomes.