BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling.
Sanchez-Laorden, Berta Viros, Amaya Girotti, Maria Romina Pedersen, M Saturno, Grazia Zambon, A Niculescu-Duvaz, D Turajlic, Samra Hayes, A Gore, Martin
Sanchez-Laorden, Berta
Viros, Amaya
Girotti, Maria Romina
Pedersen, M
Saturno, Grazia
Zambon, A
Niculescu-Duvaz, D
Turajlic, Samra
Hayes, A
Gore, Martin
Citations
Altmetric:
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.
Description
Date
2014-03-25
Publisher
Collections
Keywords
Type
Article
Citation
BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. 2014, 7 (318):ra30 Sci Signal