Drug network derived from the core EGFR interactome and combination strategy to overcome the resistant cells. Drug network derived from the core EGFR interactome.

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Drug network derived from the core EGFR interactome and combination strategy to overcome the resistant cells. Drug network derived from the core EGFR interactome and combination strategy to overcome the resistant cells. (A) Blue rectangles indicate core network proteins (N=14), and 1520 red hexagon nodes represent compounds. Orange lines between drug and protein indicate the relationships derived by the literature‐reported interactions. (B) Kinase inhibitors derived from competition binding assays were integrated to the core network. Blue nodes=EGFR‐specific core proteins for cell survival and red nodes=non‐specific core proteins in the EGFR interactome; rectangles=baits; ellipses=prey or protein identified by phosphoproteomics; orange lines=binding interactions between the inhibitor and the particular protein. The inhibitors are indicated by hexagons, with colors related to Kd shown at bottom right. (C) In vitro kinase assay results using purified EGFR kinases from indicated alleles were assessed after incubation with indicated concentration of midostaurin. Kinase activity results are shown as a percentage compared to DMSO control. (D) Lysates from either PC9 or PC9GR cells were incubated with immobilized midostaurin, and unique peptides corresponding to EGFR or other validated midostaurin target proteins (AMPK1α and PDPK1) were quantified. Number of unique peptides is shown for each protein. (E) The cells were exposed to erlotinib (Erlo), midostaurin (Mido), or combination at indicated concentrations. Signaling changes were evaluated by western blotting after 4 h treatment. (F) Indicated cells, including H157 cells with wild‐type EGFR, were treated with 500 nM erlotinib, 1000, nM midostaurin, 500 nM CEP‐701, or combination with erlotinib at the same concentration for 24 h. PARP cleavage was evaluated by western blotting (left panel) and caspase 3 activity measured by flow cytometry (right panel) are means±s.d. for triplicate data points. ‘**’: P<0.01; ‘*’: P<0.05 comparing combination treatment with other single treatment. In (E and G), equal protein loading was confirmed by β‐actin evaluation. (G) Cells were exposed to titration concentration of erlotinib, midostaurin, and combination of erlotinib with midostaurin or (H) Cells were exposed to titration concentration of erlotinib, CEP‐701, and combination of erlotinib with CEP‐701 at the same rate concentrations. The cell viability was assessed by CellTiter Glo after 5‐day treatment. The growth curves were constructed by GraphPad Prism 6 and combination index (CI) was calculated by the CompuSyn software ( http://www.combosyn.com/). CI<1 represents synergism in drug combinations and was labeled below the curve of combination group. Jiannong Li et al. Mol Syst Biol 2013;9:705 © as stated in the article, figure or figure legend