Modeling critical dosing strategies for stromal-induced resistance to cancer therapy.

Complex interactions between stromal cells, tumor cells and therapies can influence environmental factors that in turn impact anticancer treatment efficacy. Disentangling these phenomena is critical for understanding treatment response and designing effective dosing strategies. We propose a mathematical model for a common tumor-stromal interaction motif where stromal cells secrete factors that promote drug resistance. We demonstrate that the presence of this interaction modulates the therapeutic dose window of efficacy and can lead to nonmonotonic treatment response. We consider combination strategies that target stromal cells and their secretome, and identify strategies that constrain drug concentrations within the efficacious window for long-term response. We explore an experimental dataset from colorectal cancer cells treated with anti-EGFR targeting therapy, cetuximab, where cancer-associated fibroblasts increase epidermal growth factor secretion under treatment. We apply our general approach to identify a critical drug concentration threshold and study effective dosing regimens for single-drug and combination therapies.