Research ArticleCancer

BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells by Reactivating MEK and ERK Signaling

Sci. Signal.  25 Mar 2014:
Vol. 7, Issue 318, pp. ra30
DOI: 10.1126/scisignal.2004815

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Blocking Melanoma Metastasis

Although inhibitors of the mutant BRAF kinase are effective in some melanoma patients, intrinsic or acquired resistance to the drug is common. Furthermore, the growth of melanoma tumors with concomitant mutations in guanosine triphosphatase RAS, which activated kinases in the RAF family, is paradoxically accelerated by BRAF inhibition. RAF is the first kinase in a three-kinase cascade [the RAF–MEK (mitogen-activated protein kinase kinase)–ERK (extracellular signal–regulated kinase) pathway] that is involved in cell proliferation. Using proteomics, patient material, and mouse models, Sanchez-Laorden et al. found that BRAF inhibition paradoxically stimulated MEK and ERK signaling to induce metastasis of melanoma cells with mutant BRAF, resistance to a BRAF inhibitor, or mutant RAS. Combined treatment with a MEK inhibitor prevented BRAF inhibitor–induced metastasis in mice. Thus, combination therapies may be best to prevent both primary tumor growth and drug-induced metastasis.