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BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling.

Research paper by Berta B Sanchez-Laorden, Amaya A Viros, Maria Romina MR Girotti, Malin M Pedersen, Grazia G Saturno, Alfonso A Zambon, Dan D Niculescu-Duvaz, Samra S Turajlic, Andrew A Hayes, Martin M Gore, James J Larkin, Paul P Lorigan, Martin M Cook, Caroline C Springer, Richard R Marais

Indexed on: 29 Mar '14Published on: 29 Mar '14Published in: Science signaling



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.

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