dc.contributor.author | Lionarons, DA | en_US |
dc.contributor.author | Hancock, DC | en_US |
dc.contributor.author | Rana, S | en_US |
dc.contributor.author | East, P | en_US |
dc.contributor.author | Moore, C | en_US |
dc.contributor.author | Murillo, MM | en_US |
dc.contributor.author | Carvalho, J | en_US |
dc.contributor.author | Spencer-Dene, B | en_US |
dc.contributor.author | Herbert, E | en_US |
dc.contributor.author | Stamp, G | en_US |
dc.contributor.author | Damry, D | en_US |
dc.contributor.author | Calado, DP | en_US |
dc.contributor.author | Rosewell, I | en_US |
dc.contributor.author | Fritsch, R | en_US |
dc.contributor.author | Neubig, RR | en_US |
dc.contributor.author | Molina-Arcas, M | en_US |
dc.contributor.author | Downward, J | en_US |
dc.date.accessioned | 2020-06-03T11:42:32Z | |
dc.date.issued | 2019-07 | |
dc.identifier.citation | Cancer cell, 2019, 36 (1), pp. 68 - 83.e9 | |
dc.identifier.issn | 1535-6108 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3689 | |
dc.identifier.eissn | 1878-3686 | |
dc.identifier.doi | 10.1016/j.ccell.2019.05.015 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 68 - 83.e9 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Melanocytes | |
dc.subject | Animals | |
dc.subject | Mice, Transgenic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Melanoma | |
dc.subject | Cell Transformation, Neoplastic | |
dc.subject | Disease Models, Animal | |
dc.subject | rac1 GTP-Binding Protein | |
dc.subject | Proto-Oncogene Proteins B-raf | |
dc.subject | Serum Response Factor | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Prognosis | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Amino Acid Substitution | |
dc.subject | Cell Survival | |
dc.subject | Gene Expression | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Alleles | |
dc.subject | Models, Biological | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Epithelial-Mesenchymal Transition | |
dc.title | RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-24 | |
rioxxterms.versionofrecord | 10.1016/j.ccell.2019.05.015 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer cell | |
pubs.issue | 1 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Experimental Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 36 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Experimental Pathology | en_US |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Stamp, Gordon | en |
dc.contributor.icrauthor | Downward, Julian David Harry | en |