RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.
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ICR Authors
Authors
Lionarons, DA
Hancock, DC
Rana, S
East, P
Moore, C
Murillo, MM
Carvalho, J
Spencer-Dene, B
Herbert, E
Stamp, G
Damry, D
Calado, DP
Rosewell, I
Fritsch, R
Neubig, RR
Molina-Arcas, M
Downward, J
Hancock, DC
Rana, S
East, P
Moore, C
Murillo, MM
Carvalho, J
Spencer-Dene, B
Herbert, E
Stamp, G
Damry, D
Calado, DP
Rosewell, I
Fritsch, R
Neubig, RR
Molina-Arcas, M
Downward, J
Document Type
Journal Article
Date
2019-07
Date Accepted
2019-05-24
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 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.
Citation
Cancer cell, 2019, 36 (1), pp. 68 - 83.e9
Source Title
Publisher
ISSN
1535-6108
eISSN
1878-3686
Research Team
Experimental Pathology
Lung Cancer Group
Lung Cancer Group