RAC1 Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.

RAC1 Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.

Publication date: Jul 08, 2019

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 RAC1 in melanoma development and reveal that RAC1 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 RAC1 from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1 cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1 also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1 as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.

Lionarons, D.A., Hancock, D.C., Rana, S., East, P., Moore, C., Murillo, M.M., Carvalho, J., Spencer-Dene, B., Herbert, E., Stamp, G., Damry, D., Calado, D.P., , Rosewell, Fritsch, R., Neubig, R.R., Molina-Arcas, M., and Downward, J. RAC1 Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. 23319. 2019 Cancer Cell (36):1.

Concepts Keywords
AKT Melanoma Therapy
BRAF Lymphoma
Codon Melanoma
Endogenous RAC1 promoter melanoma
Locus Melanoma
Lymphoma Cancer
Melanocytes RAC1
Melanoma BRAF
Mesenchymal Medicine
NF1
Oncogenic
Phenotypic
RAC1
Tumorigenesis

Semantics

Type Source Name
gene UNIPROT PTEN
gene UNIPROT TP53
gene UNIPROT SLC22A3
gene UNIPROT ITK
disease MESH tumorigenesis
gene UNIPROT NF1
disease DOID lymphoma
disease MESH lymphoma
gene UNIPROT SRF
pathway BSID Gene Expression
gene UNIPROT AKT1
gene UNIPROT NRAS
gene UNIPROT BRAF
disease DOID cutaneous melanoma
gene UNIPROT SYF2
gene UNIPROT PRTN3
gene UNIPROT PRDX6
disease MESH Development
pathway BSID Melanoma
disease DOID Melanoma
disease MESH Melanoma
gene UNIPROT RNASE1
gene UNIPROT RAC1

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