Research ArticleCancer

Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration

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Sci. Signal.  05 Aug 2014:
Vol. 7, Issue 337, pp. ra73
DOI: 10.1126/scisignal.2005484

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Overcoming the RAF Inhibitor Paradox

ARAF, BRAF, and CRAF, which are kinases of the RAF family and can form complexes with each other, are activated by RAS and participate in pathways that stimulate cell proliferation. Mutations in RAS or BRAF drive cancer. Inhibitors of BRAF or BRAF-CRAF complexes are used clinically in cancers with mutant BRAF. However, these inhibitors paradoxically activate downstream proteins, leading to drug resistance and tumor metastasis, especially in tumors that have mutations in RAS. Mooz et al. found that ARAF had similar functions to CRAF and mediated the drug-induced paradoxical signaling in lung and pancreatic cancer cell lines, regardless of whether the cells also had RAS mutations. Preventing the production of ARAF or its interaction with itself (homodimerization) blocked downstream signaling, cell migration, and tumor invasion induced by BRAF inhibitors, suggesting that targeting ARAF may improve therapeutic outcomes for some cancers with RAS and BRAF mutations.