Abstract 692: Drug treatment causes evolution

Abstract

Abstract A targeted drug treatment, PLX40720, eliminates the bulk of melanoma tumours, but there is always regression. We assert that the tumour population is heterogenous. Then the drug treatment is a selection process, targeting specific subpopulations. When the treatment ends, phenotypic drift causes reversion towards the original wild-type population. Our model is a discrete population of cells. The cells each have a distinct phenotype. This phenotype determines their fitness. The fitness changes under drug conditions: we define a fitness landscape for both drug and drug-free conditions. We validate the model using population experiments on four melanoma cell lines (1205Lu, WM164, WM793, WM983A). We find initial growth curves, death rates and regrowth curves under drug treatment. Matching the clinical approach, we treat the cell lines chronically with drug for six months. We then stop treatment and examine the reversion of the resistant cell lines to wild-type over a period of several weeks. There is only partial reversion to wild-type. We return to the model to incorporate this experimental data. We extend the complexity of the fitness landscape to multiple fitness “wells". Reversion after drug treatment only populates one of these wells. This more complex landscape reproduces the experimental observations. The model concept extends naturally to considering combination therapies. We also discuss the effect of modifying the local environment of the tumour: the drug treatment may become more effective. This approach gives a quantitative assessment of treatment strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 692. doi:10.1158/1538-7445.AM2011-692