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Background: Melanoma has high metastatic potential and commonly develops resistance to therapy. According to the SEER Cancer Database, 97,610 new cases and 7,990 deaths are expected in 2023. We have shown abnormal activation of ADP-ribosylation factor 6 (ARF6) in melanoma development, showing its potential as a therapeutic target. We previously published that ARF6 activation is sufficient to accelerate metastasis in Dct-TVA::Braf V600E; Cdkn2aflox/flox murine melanoma. Our unpublished data reveals that melanocyte-specific deletion of Arf6 in Dct-TVA::Braf V600E; Cdkn2aflox/flox murine melanoma significantly reduces tumorigenesis and progression, demonstrating a novel role for ARF6 in early-stage tumor progression. Overall, these data suggest that ARF6 promotes tumor cell survival and/or proliferation. Our preliminary data demonstrate that ARF6 is critical for cell survival. The goal of this project is to specifically test the role for ARF6 in proliferation. ||Hypothesis: ARF6 activation promotes proliferation in human melanoma. ||Methods: A375 human melanoma cells (BRAFV600E) were plated in a 96 well plate (2000 cells per well) and allowed to attach overnight. Cells were treated with vehicle (DMSO) vs. QS11 (ARF6 agonist) at varying doses. First, we tested a dose response with 10 drug concentrations and collected viability data at 24hr, 48hr, and 72hr. From these data, we determined an IC50 (~2.5μM) and settled upon testing 2μM and 1μM (non-toxic) for the final assays. Cell viability data were collected at 0hr, 6hr, 12hr, 24hr, 48hr, and 72hr timepoints. We performed Luminescent Cell Viability Assays. ||Results: 2μM QS11 inhibits cell viability, as expected based on our dose response experiment, due to nonspecific toxicity. 1μM of QS11 fails to enhance proliferation. ||Conclusion: At this time, we do not have any evidence that ARF6 activation promotes proliferation. This is in contrast to our preliminary data showing that ARF6 is critical for tumor cell survival. Therefore, the role of ARF6 in tumor progression may be limited to cell survival