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.

From both short- and long-term drug treatment regimens, AKT1Q79K expression conferred vemurafenib resistance robustly in M229 cells but weakly in M238 and WM2664 cells (as well as M263 and M249 cells; Supplementary Fig. S8)….Given that AKT1Q79K expression in M229 cells amplified BRAFi-induced p-AKT (Thr308) and conferred vemurafenib resistance...