Increased PI3K AKT signaling is one previously recognized process of resistance to BRAF inhibition. In our experiments, activation of ALK inhibitor AKT was seen irrespective of PTEN status, that has been proven to be one determinant of responsiveness to BRAF inhibition. Consistent with the importance of AKT signaling in a reaction to RAF inhibitors, we discovered that right inhibiting AKT with MK2206 was able to enhance the effectiveness of PLX4032 and ablate the protective effects of WM115 cells and NRG1??on 1205Lu. These data also show that AKT is one of the primary effectors of ERBB3 mediated resistance to PLX4032. Curiously, inhibition of both BRAF or MEK1/2 generated the decreased phosphorylation of S6 ribosomal protein. This restoration of protein translation along with the activities of AKT on apoptotic erythropoetin and cellcycle proteins may donate to the enhanced cell viability. Previous reports have highlighted the up-regulation of RTKs, such as IGF1R or PDGFR, in melanoma as possible mechanisms of resistance to RAF inhibitors. We didn’t find superior signaling from either RTK in reaction to their respective ligands when cells were pre-treated with PLX4032 for 24-hours. This would suggest that these receptors become overexpressed or hyperactivated later in the development of resistance. Indeed, the adaptive mechanism we propose likely allows cells to continue until they get a permanent mechanism of resistance. In line with this idea, ERBB3 shows enhanced signaling within a natural compound library few hours of drug treatment. We also observed a marked upsurge in phospho ERBB3 in xenografts after 5 day treatment with PLX4720, showing in vivo significance. Increased ERBB3 phosphorylation was also detected in 2 out of 3 on treatment individual products available to us. Curiously, vemurafenib associated improved ERBB3 phosphorylation was also detected in 4 out of 11 progressing people, and thus, it could be associated with acquired resistance sometimes. Basal ERBB3 expression was variable across cell lines, and it’s therefore likely that the upregulation of ERBB3, compared to its basal expression, modulates the reaction to RAF inhibitor. In addition, endogenous NRG1 was expressed at extremely low levels in cancer cells and was not increased following treatment with RAF inhibitor. The notion that paracrine activation of ERBB3 occurs is supported by evidence that creation of NRG1 from dermal fibroblasts influences melanocyte biology.