Many genes have recently been discovered that, when mutated, promote the development of malignant melanoma. Such discoveries are important, as they can point the way towards specific treatments. Recently, two new genes were discovered to cause melanoma in response to sun-damage: PREX2 and RAC1. We recently showed that melanoma cells with these mutations do not respond to drugs such as vemurafinib, even if the cells also have BRAF mutations, but do respond to inhibitors of a protein called Pak. We believe that such anti-Pak drugs could be useful specifically in patients who have the PREX2 or RAC1 mutation, but we lack good cell-based or animal-based models to test this idea. In the first aim of this proposal, we evaluate a cellular model of RAC1-driven melanoma, comparing its drug sensitivity to that of matched BRAF and NRAS-mutant cells. In addition, since melanoma cells are known to acquire resistance to “targeted” agents, we will use a new method to determine how these cells adapt to evade these drugs. In the second aim, we construct a new mouse model of melanoma by altering the RAC1 gene in melanocytes, which we expect will cause the mice to develop melanoma over the course of a few months. This animal model can then be used to evaluate the efficacy of anti-melanoma drugs such as Pak inhibitors and others.