RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.
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Date
2019-07Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Melanocytes
Animals
Mice, Transgenic
Humans
Mice
Melanoma
Cell Transformation, Neoplastic
Disease Models, Animal
rac1 GTP-Binding Protein
Proto-Oncogene Proteins B-raf
Serum Response Factor
Protein Kinase Inhibitors
Prognosis
Xenograft Model Antitumor Assays
Amino Acid Substitution
Cell Survival
Gene Expression
Drug Resistance, Neoplasm
Mutation
Alleles
Models, Biological
Female
Male
Epithelial-Mesenchymal Transition
Research team
Experimental Pathology
Lung Cancer Group
Language
eng
Date accepted
2019-05-24
License start date
2019-07
Citation
Cancer cell, 2019, 36 (1), pp. 68 - 83.e9