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RAC1P29S induces a mesenchymal phenotypic switch via serum response factor to promote melanoma development and therapy resistance

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posted on 28.10.2020, 14:02 by Daniël A Lionarons, David C Hancock, Sareena Rana, Philip East, Christopher Moore, Miguel M Murillo, Joana 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.

Funding

Crick (Grant ID: 10070, Grant title: Downward FC001070) Crick (Grant ID: 10057, Grant title: Calado FC001057) Crick (Grant ID: 10002, Grant title: Stewart FC001999) Crick (Grant ID: 10009, Grant title: Nye FC001999) Crick (Grant ID: 10019, Grant title: Rosewell FC001999)

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