<p>(A) The growth dynamics of all in silico cells treated with various therapies for three months in a homogeneous and resource-limited microenvironmental condition. A color line at each treatment indicates the most dominant cell after a given therapy. Color-shaded boxes indicate treatments selecting for the same dominant in silico cell. Orange box: dominant cell (cell ID: 342) after treatments of EGFRi/METi, EGFRi/AKTi, METi/AKTi, EGFRi/RAFi, and AKTi/RAFi. Red box: dominant cell (ID: 417) after <i>RAS_m</i>i/METi and AKTi. Yellow box: dominant cell (ID: 337) after EGFRi/MEKi, METi/MEKi, and AKTi/MEKi. Blue box: dominant cell (ID: 36) after RAFi/MEKi, MEKi, RAFi/ERKi, and MEKi/ERKi. Purple box: dominant cell (ID: 156) after EGFRi/ERKi, METi/ERKi, and AKTi/ERKi. Green box: dominant cell (ID: 113) after ERKi and ERKi/<i>RAS_mi</i>. (B) Linear relationship between average relative cell viability (log2 scale) and post-treatment Shannon indexes. Linear correlation constant: 0.65. Square: monotherapy; circle: combination therapy. Red: EGFRi alone or combination with METi, <i>RAS_mi</i>, AKTi, RAFi, MEKi, or ERKi. Blue: METi alone or combination with <i>RAS_m</i>i, AKTi, RAFi, MEKi, or ERKi. Pink: <i>RAS_m</i>i alone or combination with RAFi, AKTi, MEKi, or ERKi. Green: AKTi alone or combination with RAFi, MEKi, or ERKi. Gray: RAFi, RAFi/MEKi, RAFi/ERKi. Yellow: MEKi, MEKi/ERKi. Orange: ERKi. (C) Linear relationship between average relative cell viability (log2 scale) and post-treatment (with HGF stimulation) Shannon indexes. Linear correlation constant: 0.63. Square: monotherapy; circle: combination therapy. Color definitions are the same as panel B. (D) Therapies affected by HGF significantly. Each arrow starts from a point without HGF stimulation to a point with HGF stimulation. Gray: RAFi/ERKi and RAFi/MEKi. Blue: <i>RAS_m</i>i, <i>RAS_m</i>i/AKTi, <i>RAS_m</i>i/ERKi. Red: EGFRi, EGFRi/<i>RAS_m</i>i, EGFRi/AKTi, EGFRi/MEKi, and EGFRi/ERKi. The numerical data used in Fig 6 are included in the fifth 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; corr, linear correlation; EGFR, epidermal growth factor receptor; ERK, extracellular receptor kinase; HGF, hepatocyte growth factor; MEK, mitogen-activated protein kinase kinase; MET (c-MET), tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR); PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; RAS_m, mutated RAS; RAS_w, wild-type RAS.</p
