We analyzed 100 tumor samples from 44 patients (median progression free survival or PFS = 145 days; range = 84 to 489) (Table 1; Fig. 1A; Supplementary Fig. S1 and Table S1) whose melanomas developed acquired resistance to either vemurafenib or dabrafenib monotherapy....We also tested whether the detected functional molecular alterations would alter BRAF inhibitor sensitivity (Fig. 3C). Whereas AKT1 wild type over-expression had no effect on vemurafenib sensitivity, AKT1 Q79K or E17K and AKT3 E17K over-expression conferred vemurafenib resistance.

In M229 cells, where AKT1Q79K and AKT1E17K expression conferred a two-log increase in BRAFi resistance, the expression of AKT1 WT led to no significant change in BRAFi sensitivity.