Genetic alterations in the PI3K–PTEN–AKT pathway detected during disease progression and their functional impacts. Genetic alterations in the PI3K–PTEN–AKT.

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Genetic alterations in the PI3K–PTEN–AKT pathway detected during disease progression and their functional impacts. Genetic alterations in the PI3K–PTEN–AKT pathway detected during disease progression and their functional impacts. A, immunoblotting of protein lysates from BRAFV600E human melanoma cell lines (M229, WM2664, M249, and VUB MEL A, B, and C) stably expressing the indicated WT or mutant genes and their impacts on phospho-AKT (also shown are total levels and Tubulin serving as loading controls). B, phospho-AKT (Ser473; brown, left two panels; gray/black, right three panels) staining by immunohistochemistry (bar, 50 μm) in melanoma tissues harboring indicated genetic alterations in the PI3K–PTEN–AKT pathway during disease progression (relative to staining in melanomas before BRAF inhibitor therapy). fs, frameshift. C, the effects of stable overexpression of indicated AKT1/3, PIK3CA, PIK3R2, and PTEN constructs or stable PTEN knockdown (vs. empty vectors) on cellular sensitivity to vemurafenib-mediated growth suppression (error bars, SEM; P values of log EC50 of each construct vs. vector: AKT1 WT 0.2984, E17K 0.0006, Q79K 0.0001; AKT3 WT 0.0064, E17K 0.0033; PIK3CA WT < 0.0001, D350G 0.0148, E545G < 0.0001, E545K < 0.0001; PIK3R2 WT 0.8262, N561D < 0.0001). Hubing Shi et al. Cancer Discovery 2014;4:80-93 ©2014 by American Association for Cancer Research