RAC1P29S induces a mesenchymal phenotypic switch via serum response factor to promote melanoma development and therapy resistanceMore about Open Access at the Crick
Authors listDaniël A Lionarons David Hancock Sareena Rana Philip East Christopher Moore Miguel Murillo Joana Do Vale Viegas Silva Carvalho Bradley Spencer-Dene Eleanor Herbert Gordon Stamp Djamil Damry Dinis Calado Ian Rosewell Ralph Fritsch Richard Neubig Miriam Molina Arcas Julian Downward
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 RAC1P29S in melanoma development and reveal that RAC1P29S 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 RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.
Journal Cancer Cell
Issue number 1