Journal
SCIENCE SIGNALING
Volume 7, Issue 318, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2004815
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Funding
- Federation of European Biochemical Societies Long-Term Fellowship
- European Organization for Research and Treatment of Cancer (EORTC) Melanoma Group
- Tegger Foundation
- Wenner-Gren Foundations, Stockholm
- International Association of Cancer Research [09-0773]
- Harry J. Lloyd Charitable Trust
- National Health Service (NHS)
- Cancer Research UK [C5759/A12738, C107/A10433, C309/A2187]
- ICR
- Cancer Research UK Manchester Institute
- Cancer Research UK [17240, 19279, 11566] Funding Source: researchfish
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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.
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