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dc.contributor.authorSanchez-Laorden, Berta
dc.contributor.authorViros, Amaya
dc.contributor.authorGirotti, Maria Romina
dc.contributor.authorPedersen, M
dc.contributor.authorSaturno, Grazia
dc.contributor.authorZambon, A
dc.contributor.authorNiculescu-Duvaz, D
dc.contributor.authorTurajlic, Samra
dc.contributor.authorHayes, A
dc.contributor.authorGore, Martin
dc.contributor.authorLarkin, J
dc.contributor.authorLorigan, Paul C
dc.contributor.authorCook, M
dc.contributor.authorSpringer, C
dc.contributor.authorMarais, Richard
dc.date.accessioned2014-06-11T08:26:58Z
dc.date.available2014-06-11T08:26:58Z
dc.date.issued2014-03-25
dc.identifier.citationBRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. 2014, 7 (318):ra30 Sci Signalen
dc.identifier.issn1937-9145
dc.identifier.pmid24667377
dc.identifier.doi10.1126/scisignal.2004815
dc.identifier.urihttp://hdl.handle.net/10541/320636
dc.description.abstractMelanoma is a highly metastatic and lethal form of skin cancer. The protein kinase BRAF is mutated in about 40% of melanomas, and BRAF inhibitors improve progression-free and overall survival in these patients. However, after a relatively short period of disease control, most patients develop resistance because of reactivation of the RAF-ERK (extracellular signal-regulated kinase) pathway, mediated in many cases by mutations in RAS. We found that BRAF inhibition induces invasion and metastasis in RAS mutant melanoma cells through a mechanism mediated by the reactivation of the MEK (mitogen-activated protein kinase kinase)-ERK pathway, increased expression and secretion of interleukin 8, and induction of protease-dependent invasion. These events were accompanied by a cell morphology switch from predominantly rounded to predominantly elongated cells. We also observed similar responses in BRAF inhibitor-resistant melanoma cells. These data show that BRAF inhibitors can induce melanoma cell invasion and metastasis in tumors that develop resistance to these drugs.
dc.language.isoenen
dc.rightsArchived with thanks to Science signalingen
dc.titleBRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling.en
dc.typeArticleen
dc.contributor.departmentMolecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BXen
dc.identifier.journalScience Signalingen
html.description.abstractMelanoma is a highly metastatic and lethal form of skin cancer. The protein kinase BRAF is mutated in about 40% of melanomas, and BRAF inhibitors improve progression-free and overall survival in these patients. However, after a relatively short period of disease control, most patients develop resistance because of reactivation of the RAF-ERK (extracellular signal-regulated kinase) pathway, mediated in many cases by mutations in RAS. We found that BRAF inhibition induces invasion and metastasis in RAS mutant melanoma cells through a mechanism mediated by the reactivation of the MEK (mitogen-activated protein kinase kinase)-ERK pathway, increased expression and secretion of interleukin 8, and induction of protease-dependent invasion. These events were accompanied by a cell morphology switch from predominantly rounded to predominantly elongated cells. We also observed similar responses in BRAF inhibitor-resistant melanoma cells. These data show that BRAF inhibitors can induce melanoma cell invasion and metastasis in tumors that develop resistance to these drugs.


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