Figure 2. Experimental observations motivate a nonlinear ordinary differential equation model for cancer therapy.

System states (shown in black bold capital font) represent the nonlinear dynamic behavior of (i) uninfected cancer cell density, C [cells/cm2], (ii) MEK-inhibition induced G1 arrest cell density, C_G1 [cells/cm2], (iii) untreated and infected cell density, IC [cells/cm2], and (iv) treated and infected cell density, IC_T [cells/cm2]. Parameter values (shown in red italic script) govern treatment/infection dependent state transitions (solid black arrows) that direct proliferation (σ), G1 cell cycle arrest/release, infection (β_n), and lysis (δ_n), where n denotes whether these cells infect/lyse from a treated (n = T or n = T·G1) or untreated (n = ‘blank’) state. Corresponding delay terms are shown in gray font. MEK-inhibition is described as a reversible process since cells undergo G1 arrest via CI1040 treatment and release upon removal of MEK-inhibitor by media change, returning to the proliferating state (dashed block arrow). Infection is an irreversible process that ultimately results in cell death (solid block arrow).