Metastatic melanoma is the cause of more than 8000 deaths a year in the US alone. Activating mutations at the V600 codon of the BRAF kinase gene occur in approximately 50% of metastatic melanomas. Recently, a selective small-molecule inhibitor of mutant BRAF, vemurafenib, was FDA-approved because in a randomized phase 3 clinical trial, vemurafenib prolonged survival significantly in patients with V600EBRAF-mutant melanoma compared to dacarbazine chemotherapy. Nevertheless, resistance to vemurafenib develops and disease control is relatively short lived with a median progression-free interval of 6-7 months highlighting the need for combination treatment regimens to provide more durable outcomes. Although clinical trials assessing treatment regimens that combine a MEK inhibitor with a BRAF inhibitor are showing promising results, several MEK-independent mechanisms of BRAF inhibitor resistance have been identified. The Mel-RMUs cell line has aquired resistance to the V600EBRAF inhibitor, PLX4720 (an analog of vemurafenib) during continuous in vitro culture. A previous study demonstrated that Mel-RMUs survival did not depend on MEK while serum starvation, inhibition of PI3K/Akt, and inhibition of ERK1/2 reduced viability of these cells. Notably, no treatment was identified that could completely overcome resistance to inhibition with PLX4720 and the mechanism of resistance remains unclear. Here, we demonstrate that Mel-RMUs cells have aquired activation of the Axl and Insulin receptor tyrosine kinases and that these kinases remain activated even when the drug has been withdrawn for up to 25 days. We are currently exploring kinase inhibitor combinations that may overcome resistance to apoptosis and thus aid in elucidating the mechanism of MEK-independent resistance to BRAF inhibition that resides in the Mel-RMUs cell line.