Abstract
RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1$^{P29S}$ in melanoma development and reveal that RAC1$^{P29S}$ activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1$^{P29S}$ from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1$^{P29S}$ cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1$^{P29S}$ also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1$^{P29S}$ as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.