Fig 2: Inhibition of the RTK-activity of the EGFR by the pan-ErbB-inhibitor Canertinib (CI-1033) suppresses UV-induced papillomatosis in K14-HPV8E6 transgenic mice. (A) Immunohistochemical staining of paraffin embedded sections obtained from skin of K14-HPV8E6 transgenic mice 13 days after UV-exposure with the anti-pEGFR-Y1068 or rabbit IgG isotype control (magnification 1:400). (B) Transgenic mice obtained either Canertinib (CI-1033) (20 mg/kg weight) or the same volume of PBS 4 h prior UV-irradiation followed by applications of Canertinib once daily at a dose of 10 mg/kg weight or 150 µl PBS for 24 days, as given in the time line. The pictures represent examples of the lesions from four mice treated with CI-1033 (M19, 20, 23, and M26) and from one control mouse which obtained PBS (M22). The graph beneath shows the quantification of RT-PCR results with RNA isolated from two PBS and three Canertinib-treated animals to demonstrate the expression of HPV8E6. (C) Histology with H/E staining of skin section obtained from two PBS-control (M21 and M22) and four Canertinib (CI-1033)-treated animals (M19, M20, M23, and M26) 24 days after UV-irradiation.

Fig 3: High expression of Mig-6 is correlated with poor prognosis and EMT in lung cancer. a Overall survival of lung adenocarcinoma patients was compared between Mig-6-high and Mig-6-low expression groups. Histograms of Mig-6 gene expression in lung adenocarcinoma patients. Vertical red lines designate 9.887 as the optimal cutoff of mRNA derived from the log-rank test. High mRNA expression of Mig-6 was significantly associated with a poor prognosis (hazard ratio [HR]: 1.92 [95% confidence interval (CI): 1.29–2.85]). Subgroup analysis was performed in patients with or without EGFR mutation. High mRNA expression of Mig-6 without EGFR mutation was significantly associated with poor prognosis (HR: 1.86 [95% CI: 1.19–2.9]). High mRNA expression of Mig-6 with EGFR mutation was also significantly associated with poor prognosis (HR: 2.33 [95% CI: 0.97–5.59]). b The graph displays the enrichment gene set based on the hallmark and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in the top 10% vs. bottom 10% groups of Mig-6 in lung adenocarcinoma patients. Gene Set Enrichment Analysis of the EMT, G2M checkpoint, hypoxia, TGF-ß, cell cycle, and ERBB signature genes in the high and low Mig-6 expression groups of lung adenocarcinoma patients

Fig 4: Simplified schematic representation of the ErbB model. Receptor interaction, internalization, recycling and activation of MAPK and PI3K/Akt pathways are shown. Phosphatase, Ras-GTP hydrolysis and feedback regulation are indicated by red arrows. Matrix shows properties of each receptor dimer relevant to the topology of the model; see Figure 1 in Supplementary information for further information. The prefix C on certain proteins denotes an abbreviated representation of multiple species in the model, e.g. C:Shc is composed of all receptor-bound Shc molecules, which may include ErbB1/1-Shc, ErbB1/2-Shc and so on. However, each of these Shc complexes is represented explicitly by one or more dynamic variables in the model.

Fig 5: Experimental and simulated dynamics for three cell lines, each treated with two concentrations of EGF and HRG. Twenty good fits are shown for each cell line. (A) A431, (B) H1666 and (C) H3255 were stimulated with 5 nM or 0.01 nM EGF or 5 nM or 1 nM HRG as indicated. Vertical axes denote normalized signals representing the phosphorylated (and nominally active) forms of ErbB1, ERK and Akt such that the highest measured and simulated value for one signal, across all treatment conditions, was set to 100. In each panel, the fit having the lowest value of the objective function is indicated by a bold line; slightly less good fits are indicated by faded lines. Experimental data are indicated by dots and standard error of the mean (biological triplicates) by the vertical bars. (D) Distributions of 8 parameter values across 50 independent parameter optimization runs; parameter identities are described in more detail in Supplementary information.