Model prediction and validation.

<p>(A) Histograms of relative cell viabilities (log2 scale) of all in silico cells after treatments of EGFRi, METi, <i>RAS_m</i>i, AKTi, RAFi, MEKi, and ERKi. First, a bimodal distribution EGFRi-treated in silico cells (one mode: −1.25; second mode: −0.5). Second, a skewed distribution after METi (a skew toward 0; 0: no change). Third, a uniform distribution in response to <i>RAS_m</i>i (almost uniform distribution from −1.5 to 1.5). Fourth, a slight bimodal distribution after AKTi. Fifth, a distributional response after RAFi. Sixth, a normal distribution in response to MEKi. Seventh, a normal distribution after ERKi. (B) Histograms of relative cell viabilities of all in silico cells in log2 scale. First: EGFRi only (blue), EGFRi/ERKi (orange), and EGFRi/MEKi (yellow). Second: METi only (blue), METi/ERKi (orange), and METi/MEKi (yellow). Third: <i>RAS_m</i>i only (blue), <i>RAS_m</i>i/RAFi (green), <i>RAS_m</i>i/ERKi (orange), and METi/MEKi (yellow). Fourth: AKTi only (blue), AKTi/RAFi (green), AKTi/ERKi (orange), and AKTi/MEKi (yellow). Fifth: RAFi only (blue), RAFi/ERKi (orange), and RAFi/MEKi (yellow). (C) Validation. Model predicted relative cell viabilities (red bars) and experimental data (gray bars) after 10 different treatments. First: EGFRi, EGFRi/MEKi, and EGFRi/ERKi. Second: METi, METi/MEKi, METi/ERKi. Third: AKTi, AKTi/RAFi, AKTi/MEKi, AKTi/ERKi. The numerical data used in Fig 3 are included in the second sheet <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2002930#pbio.2002930.s013" target="_blank">S1 Data</a>. AKT (PKB), protein kinase B; DMSO, Dimethyl sulfoxide (control); EGFR, epidermal growth factor receptor; ERK, extracellular receptor kinase; MEK, mitogen-activated protein kinase kinase; MET (c-MET), tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR); RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma.