FIGURE 6.

Simulation of the effect of Cetuximab and cmp4 on Ras signaling in human colorectal cancer SW48 isogenic cellular models. (A–I) In silico modeling of Ras signaling network in SW48 isogenic cellular models, expressing a hyper-activated EGF receptor mutant in combination with different Ras variants: either wild type Ras (A,D,G; SW48 KRAS ^WT/WT) or KRas^G13D (B,E,H; SW48 KRAS ^WT/G13D) or KRas^G12V (C,F,I; SW48 KRAS ^WT/G12V). The different cellular systems were simulated under untreated condition (A–C; CTRL), or treated with the following drugs: Cetuximab (D–F), used at an ideal concentration completely blocking EGFR activity, which represent the maximal effect obtainable with the single mechanism of action based on GEF-mediated nucleotide exchange inhibition; cmp4 (G–I), used at the concentration of 100 µM, which is around IC₅₀ for this compound on multilevel mechanisms of action (Supplementary Table S1). For each panel, the dimension and colour of the characters are indicative of the level of the components or their activity in the simulation. The resulting effector activity is illustrated as a histogram on the right of each panel, and its fold change normalized on wild type unstimulated cells is reported on top. For panels (D–I), the inhibition efficacy is calculated with respect to the untreated corresponding model.