Citation
- Authors: Sanchez-Laorden, B., Viros, A., Girotti, M. R., Pedersen, M., Saturno, G., Zambon, A., Niculescu-Duvaz, D., Turajlic, S., Hayes, A., Gore, M., Larkin, J., Lorigan, P., Cook, M., Springer, C., Marais, R.
- Year: 2014
- Journal: Sci Signal 7 ra30
- Applications: in vitro / siRNA / INTERFERin
- Cell types:
- Name: WM1366
Description: Human skin melanoma cells - Name: WM1791
- Name: WM1366
Method
10 nM
Abstract
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.