Melanoma is the most serious type of skin cancer that can spread to other parts of the body, where it becomes difficult to treat and can be fatal. Over half of all melanomas have a mutation in a gene called BRAF that is required for melanoma to grow. Drugs that prevent BRAF from working have improved patient survival but are still not curative. Patients inevitably develop drug resistance, resulting in disease relapse. Resistance commonly occurs due to acquisition of additional genetic and epigenetic changes that allow tumor cells to survive even when BRAF has been inactivated. Epigenetics is a process by which genes are switched on and off by proteins that change the way the genetic material, DNA, is configured within the cell. We have identified the bromodomain protein, BRD9 as a novel epigenetic protein that is required for melanoma growth. Our studies show that BRD9 is highly expressed in patient derived melanoma samples and is associated with poorer patient survival. Drugs that prevent BRD9 from working, reduce melanoma growth and enhance the antitumor effect of drugs that inactivate BRAF. We also found that inactivation of BRD9 results in changes in the expression of genes required for cancer growth and drug resistance. The studies in this MRF application will determine if combining a drug that inactivates BRD9 with a drug that inactivates BRAF is more effective than a drug that inactivates only BRAF for treating melanoma with BRAF mutations. In order to understand the therapeutic effect of BRD9 inactivation, we will investigate how BRD9 switches genes on and off.