Supplementary Figure 8 from Ultrasensitive Response Explains the Benefit of Combination Chemotherapy Despite Drug Antagonism

Supplemental Figure 8. Model parameters informed from experimental data. A) The model’s death rate was determined by treating MTA cells with lethal doses of 4-H-cyclophophamide and doxorubicin and observing that the cell population halves every 2.5 days, n=1 per condition. Cells were incubated with drugs for 3 days (represented by yellow bar) before being washed off and replaced with drug-free media. B) The model’s treated growth rate was determined by treating MTA cells with the same drug concentrations used in the concurrent vs sequential dosing experiments and observing that cells double every 2.5 days, n=1 per condition. Cells were incubated with drugs for 3 days (represented by yellow bar) before being washed off and replaced with drug-free media. C) At each simulated drug treatment (marked with yellow triangles), the model calculates the fraction of cells that will survive and the fraction that will die. Each respective cell population is modelled as growing or dying at the experimentally determined rates. Total live cell count is calculated by adding the number of growing cells with the number of dying cells over time. D) 4-H-cyclophosphamide yields about 20% viability and doxorubicin yields about 40% viability at 13% Csustained, the concentration of drug that was used in the concurrent vs sequential administration experiments (2 μM and 20 nM respectively), n=8 per condition. E) To convert experimental concentrations to dose values for the model, the corresponding dose values at 20% and 40% viability were estimated to be 1.8 for doxorubicin and 2.6 for 4-H-cyclophosphamide. F) The CH isobologram created by the model matches the experimentally determined isobologram for MTA cells in Supplemental Figure 2b when the drug interaction term is set to a sub-additive value of i = -0.8. G) Model outputs of tumor cell populations over time were fit to the experimental data to fit the level of ultrasensitivity (β = 0.4) and the level of heterogeneity in drug sensitivity (σ = 0.42).