Abstract 4307: Paradoxical activation of the MEK/ERK pathway promotes melanoma invasion and metastasis.

Melanoma is the most deadly form of skin cancer. An important feature of melanoma is its ability to metastasize and this contributes to its poor prognosis. RAS is mutated in ∼20% of melanomas and its downstream kinase BRAF is mutated in a further 50% of cases, these oncogenes regulate proliferation and survival through the MEK-ERK cascade. Selective inhibitors of BRAF such as vemurafenib have a remarkable clinical activity in patients with BRAF mutant melanomas with response rates of approximately 60-80%. In cells expressing activating BRAF mutations, vemurafenib blocks activation of the MAPK pathway. However, in cells expressing wild type BRAF and constitutively active upstream components that activate the MAPK pathway, BRAF inhibitors drive the paradoxical activation of this pathway. Here we show that kinase-dead BRAF promotes melanoma cell invasion and metastasis in the presence of oncogenic RAS. Notably, drugs that target BRAF mimic these effects and also induce RAS mutant melanoma cell invasion. The underlying mechanism is driven by paradoxical activation of the MEK-ERK pathway, resulting in increased secretion of the chemokine IL8 and subsequent secretion of extracellular matrix proteases, which induce invasion. We also show that BRAF inhibitors promote melanoma metastasis in an allograft model and that BRAF inhibitors induce invasion of drug-resistant BRAF mutant melanoma cells. We conclude that paradoxical activation of the MAPK pathway by BRAF inhibitors can drive melanoma invasion and metastasis in RAS mutant melanoma and in drug-resistant BRAF mutant melanoma cells. Citation Format: Berta Sanchez-Laorden, Amaya Viros, Maria Romina Girotti, Matthew Martin, Malin Pedersen, Alfonso Zambon, Dan Niculescu-Duvaz, Caroline Springer, Richard Marais. Paradoxical activation of the MEK/ERK pathway promotes melanoma invasion and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4307. doi:10.1158/1538-7445.AM2013-4307