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RAC1(P29S) Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

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, DP; Rosewell, I; Fritsch, R; Neubig, R R; Molina-Arcas, M; Downward, J

Authors

D A Lionarons

D C Hancock

S Rana

P East

C Moore

M M Murillo

J Carvalho

B Spencer-Dene

E Herbert

G Stamp

D Damry

DP Calado

I Rosewell

R Fritsch

R R Neubig

M Molina-Arcas

J Downward



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

Lionarons, D. A., Hancock, D. C., Rana, S., East, P., Moore, C., Murillo, M. M., …Downward, J. (in press). RAC1(P29S) Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. Cancer Cell, 36(1), 68. https://doi.org/10.1016/j.ccell.2019.05.015

Journal Article Type Article
Acceptance Date May 24, 2019
Deposit Date Jul 27, 2019
Publicly Available Date Jul 30, 2019
Journal Cancer Cell
Print ISSN 1535-6108
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 36
Issue 1
Pages 68
DOI https://doi.org/10.1016/j.ccell.2019.05.015
Public URL https://rvc-repository.worktribe.com/output/1382176

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