IGF 1R blocks full activation of MEK1/2 by inhibiting phosphorylation of S217 and shows no major activity against _200 unique kinases when tested at 10 mM. Treatment with 212 restricted ERK phosphorylation and reduced viability in both resistant and adult cell lines. In keeping with these information, MEK inhibition by 212 triggered G0/G1 cell cycle arrest angiogenesis in vivo in resistant and adult melanomas. But, a 10 fold higher dose of 212 was required to prevent ERK phosphorylation, cell viability, and G0/G1 cell cycle arrest in Mel1617 Dhge cells. Curiously, while treatment with 212 significantly increased the number of cells in SubG1 in the adult cells, it didn’t have a large influence on the resistant cells. Additional MEK inhibitors were used two by us displaying different mechanisms of action, to verify our findings with 212. Treatment of adult and immune cells with AZD6244 or UO126 led to inhibition of ERK phosphorylation, Eumycetoma G0/G1 cell cycle arrest and decreased cell viability. Similar to the outcome with 212, a 10 fold higher amount of AZD6244 was needed to inhibit phosphorylation of ERK and viability of Mel1617R cells in comparison to their adult counterparts. Therapy of 885 resistant and sensitive melanomas in a context with 212, AZD6244, or U0126 more than 72 hr showed that both adult and 885 resistant cells were partially sensitive to MEK inhibition when maintained in a 3D cancer like microenvironment. These results suggest that although ERK activity remains vulnerable to MEK inhibition in BRAF inhibitor immune cells, abrogating MAPK signaling has mainly cytostatic effects and increases the possibility that additional pathways might increase survival of these cells. To analyze if additional paths were stimulated in a reaction to chronic BRAF inhibition, we examined the activation of a few tyrosine kinase receptors. Research of RTK phosphorylation using an antibody array proposed that some RTKs were differentially phosphorylated GW0742 in the resistant cells in comparison to their parental counterparts. Using medicinal inhibitors of the receptors, we discovered that only treatment with the IGF 1R inhibitors cyclolignan picropodophyllin or tyrphostin AG1024 generated decreased viability of melanomas immune to BRAF inhibitors. In keeping with an established function of IGF 1 mediating growth and survival in melanoma, PPP had a partial effect decreasing possibility in both adult and resilient melanoma spheroids. We next evaluated both surface expression of IGF 1R and phosphorylation of IGF 1R at Tyr1131, which is indicative of kinase activation. Investigation of IGF 1R surface expression by flow cytometry unmasked that BRAF chemical resistant cells upregulate IGF 1R.