Taken together, these results establish RAC1P29S as a constitutively active driver of tumorigenesis and support the concept of targeting both its upstream regulators (DOCK2 and p50GAP) and downstream effectors (IQGAP1) as part of a co-inhibition strategy to suppress RAC1P29S-mediated melanoma progression, invasion, and resistance to targeted therapies. The gene discussed is IQGAP1; the disease is melanoma.