Dose dependent evolutionary game dynamics modulate competitive release in cancer therapy

Abstract

Therapeutic strategies for tumor control have traditionally assumed that maximizing reduction in tumor volume correlates with clinical efficacy. Unfortunately, this rapid decrease in tumor burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment strategies attempt to delay resistance via judicious treatments that maintain a significant treatable subpopulation. While these strategies have shown promise in recent clinical trials, they often rely on biological conjecture and intuition to derive parameters. In this study we experimentally measure the frequency-dependent interactions between a gefitinib resistant non-small cell lung cancer (NSCLC) population and its sensitive ancestor via the evolutionary game assay. We show that cost of resistance is insufficient to accurately predict competitive exclusion and that frequency-dependent growth rate measurements are required. In addition, we show that frequency-dependent growth rate changes may ultimately result in a safe harbor for resistant populations to safely accumulate, even those with significant cost of resistance. Using frequency-dependent growth rate data we then show that gefitinib treatment results in competitive exclusion of the ancestor, while absence of treatment results in a likely, but not guaranteed exclusion of the resistant strain. Finally, using our empirically derived growth rates to constrain simulations, we demonstrate that incorporating ecological growth effects can dramatically change the predicted time to sensitive strain extinction. In addition, we show that higher drug concentrations may not lead to the optimal reduction in tumor burden. Taken together, these results highlight the potential importance of frequency-dependent growth rate data for understanding competing populations, both in the laboratory and the clinic.