| Summary: | RAC1P29S is the third most common mutation in human melanoma, after oncogenic BRAF and NRAS mutations. Here, we study the role of RAC1P29S in melanoma initiation and progression. Signalling studies and functional screening reveal that RAC1P29S activates PAK, AKT and the SRF/MRTF transcription factor complex. Functionally, RAC1P29S promotes survival of cells deprived of growth factors or anchorage, linked to a gene expression profile that represents a melanocytic to mesenchymal transition. Mice with endogenous expression of RAC1P29S in the whole body develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumourigenesis and resistance to BRAF inhibitors. These findings indicate that RAC1P29S is a melanoma driver oncogene and mediator of drug resistance, while identifying downstream effectors with potential for therapeutic targeting.
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