Heterogeneous resistance mechanisms develop in response to W+T combination treatment in the EGFRL858R/T790M genetically engineered mice. Heterogeneous.

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Heterogeneous resistance mechanisms develop in response to W+T combination treatment in the EGFRL858R/T790M genetically engineered mice. Heterogeneous resistance mechanisms develop in response to W+T combination treatment in the EGFRL858R/T790M genetically engineered mice. A, phosphorylation (p) of EGFR, ERK1/2, S6, and 4EBP1 was assessed by immunohistochemistry, and instances of positive nodules adjacent to negative nodules (highlighted with dotted lines) were observed. B, total number of tumor nodules IHC positive (red) or negative (black) for EGFR, ERK, S6, and 4EBP1 phosphorylation. Percentage of positive cases is listed above each bar (n = 27). C, tumor volume of W+T–resistant tumors after treatment with a combination of WZ4002, trametinib, and Torin2. Yellow T indicates tumor mass. D, quantification of tumor volume for each mouse after initiation of W+T plus Torin2 combination treatment. E, PC9-derived cell lines tolerant to W+T (WT1, 3, and 4) were treated with 100 nmol/L WZ4002 + 30 nmol/L trametinib, and phosphorylation of EGFR, AKT, ERK1/2, and S6 was assessed. Image is representative of two independent experiments. F, viability of W+T–tolerant cell lines was assessed after the addition of 10 nmol/L Torin2 to W+T cotreatment at 72 hours (n = 3 independent experiments, mean ± SD). Erin M. Tricker et al. Cancer Discovery 2015;5:960-971 ©2015 by American Association for Cancer Research