Figure 5
Mechanism for enhancing gefitinib sensitivity of the downstream signaling steps. (A) Ratios of phosphorylated Shc to phosphorylated ERK in the presence of gefitinib with varying Mig6 effect parameters (k3, k5, k7, and k8). Total phosphorylated Shc and ERK measured at 5 minutes after EGF (10 nM) stimulation were used as the upstream output and as the downstream output, respectively. RX was defined as RX = [total phosphorylated X at α = 0.0005]/[total phosphorylated X at α = 1]. The values of RShc/RERK were calculated for each combination of two parameters selected from four Mig6 effect parameters (six combinations such as k3 &k5, k3 &k7, k3 &k8, k5 &k7, k5 &k8, and k7 &k8). In the case of k3 &k5 combination, for example, the simulation at k3 = 1 and k5 = 1 shows EGFR-WT model and the value in the k3 &k5 panel indicate RShc/RERK for k3 and k5 in L858R model A and k7 and k8 in EGFR-WT model. The other combinations are given in the similar manner. (B) Ratios of E11P/ShcP/Grb2/SOS to RasGTP, Raf1A, MEKP, MEKPP, ERKP, and ERKPP with varying k3 and k8. E11P/ShcP/Grb2/SOS measured at 5 minutes after EGF (10 nM) stimulation was used as the upstream output. RasGTP, Raf1A, MEKP, MEKPP, ERKP, and ERKPP measured at 5 minutes after EGF (10 nM) stimulation were used as the downstream output. RY is defined as RY = [Y at α = 0.0005]/[Y at α = 1]. The values of RE11P/ShcP/Grb2/SOS/RY, were calculated by using various values of k3 and k8 (Y: RasGTP, Raf1A, MEKP, MEKPP, ERKP, and ERKPP). In the case of RasGTP, for example, the simulation at k3 = 1 and k8 = 1 shows EGFR-WT model and the value in the RasGTP panel indicate RE11P/ShcP/Grb2/SOS/RRasGTP for k3 and k8 in L858R model A and k5 and k7 in EGFR-WT model. The other panels are given in the similar manner.