BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling.
Authors
Sanchez-Laorden, BertaViros, Amaya
Girotti, Maria Romina
Pedersen, M
Saturno, Grazia
Zambon, A
Niculescu-Duvaz, D
Turajlic, Samra
Hayes, A
Gore, Martin
Larkin, J
Lorigan, Paul C
Cook, M
Springer, C
Marais, Richard
Affiliation
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BXIssue Date
2014-03-25
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Melanoma 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.Citation
BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. 2014, 7 (318):ra30 Sci SignalJournal
Science SignalingDOI
10.1126/scisignal.2004815PubMed ID
24667377Type
ArticleLanguage
enISSN
1937-9145ae974a485f413a2113503eed53cd6c53
10.1126/scisignal.2004815
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