The Epidermal Growth Factor Receptor-L861Q Mutation Increases Kinase Activity without Leading to Enhanced Sensitivity Toward Epidermal Growth Factor Receptor.

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The Epidermal Growth Factor Receptor-L861Q Mutation Increases Kinase Activity without Leading to Enhanced Sensitivity Toward Epidermal Growth Factor Receptor Kinase Inhibitors Rama Krishna Kancha, MSc, Christian Peschel, MD, Justus Duyster, MD Journal of Thoracic Oncology Volume 6, Issue 2, Pages 387-392 (February 2011) DOI: 10.1097/JTO.0b013e3182021f3e Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 EGFRvIII-based assay identifies L861Q as hyperactive kinase with strongest oncogenic potential. A, Clinically relevant point mutations in EGFRvIII backbone were transiently overexpressed in HEK293 cells and analyzed for autokinase activity and Stat5 activation. B, Comparative activation of EGFR and Stat5 was quantified and plotted as fold increase in activity with respect to wild type. Analysis was done in triplicates, and measured “p values” were shown. C, Ba/F3 cells stably expressing EGFRvIII mutants were tested for their ability to outgrow untransduced cells on IL-3 withdrawal. Percentage of eGFP-positive cells was measured in triplicates at indicated time points by FACS analysis. D, NIH/3T3 cells stably expressing wild-type or mutant EGFRvIII were plated in soft agar assay at a density of 2.5 × 104 cells/well in triplicates in a six-well plate. Three weeks after plating, colonies were stained with MTT solution and counted. E, Average number of colonies for each cell line was shown. EGFR, epidermal growth factor receptor; IL, interleukin; eGFP, enhanced green fluorescent protein; FACS, fluorescence activated cell sorting; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2.5-diphenyl-2H-tetrazolium bromide. Journal of Thoracic Oncology 2011 6, 387-392DOI: (10.1097/JTO.0b013e3182021f3e) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 EGFR-L861Q is not a drug-sensitizing mutation unlike L858R and G719S. Stable Ba/F3 cell lines expressing wild-type or mutant EGFRvIII were tested for their sensitivity toward (A) gefitinib, (B) erlotinib, and (C) AEE788 at indicated concentrations. D, Table representing the effect of individual mutations on intrinsic properties of the kinase. E, Ba/F3 cells expressing wild-type or mutant EGFRvIII were treated with increasing concentrations (50, 100, 250, 500, or 1000 nM) of gefitinib or erlotinib for 30 minutes and analyzed for the inhibition of EGFR autophosphorylation and Stat5 phosphorylation. EGFR, epidermal growth factor receptor. Journal of Thoracic Oncology 2011 6, 387-392DOI: (10.1097/JTO.0b013e3182021f3e) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 EGFR-L861Q is more sensitive to WZ-4002 compared with wild-type EGFRvIII. A, Ba/F3 cells stably expressing either wild-type or mutant EGFRvIII were treated with the indicated concentrations of WZ-4002 for 48 hours and tested for cell proliferation inhibition. B, Wild-type or mutant Ba/F3-EGFRvIII cell lines were treated with increasing concentrations of WZ-4002 (50, 100, 25, 500, or 1000 nM) for 30 minutes and analyzed for inhibition of EGFR, Stat5, and extracellular signal-regulated kinase 1/2 phosphorylation. EGFR, epidermal growth factor receptor. Journal of Thoracic Oncology 2011 6, 387-392DOI: (10.1097/JTO.0b013e3182021f3e) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions