Abstract
Despite the clinical success of RAF inhibitors in BRAF-mutated melanomas, attempts to target RAF kinases in the context of RAS-driven or otherwise RAF wild-type tumours have not only been ineffective, but RAF inhibitors appear to aggravate tumorigenesis in these settings. Subsequent preclinical investigation has revealed several regulatory mechanisms, feedback pathways and unexpected enzymatic quirks in the MAPK pathway, which may explain this paradox. In this review, we cover the various proposed molecular mechanisms for the RAF paradox, the clinical consequences and strategies to overcome it.
MeSH terms
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / enzymology
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Enzyme Activation / drug effects
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Humans
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Indoles / adverse effects
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Indoles / pharmacology
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Indoles / therapeutic use
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Melanoma / drug therapy*
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Melanoma / enzymology
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Niacinamide / adverse effects
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Niacinamide / therapeutic use
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Phenylurea Compounds / adverse effects
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Phenylurea Compounds / pharmacology
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Phenylurea Compounds / therapeutic use
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Protein Multimerization / drug effects
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Protein Processing, Post-Translational
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Sorafenib
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Sulfonamides / adverse effects
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
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Vemurafenib
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raf Kinases / antagonists & inhibitors
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raf Kinases / metabolism*
Substances
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Antineoplastic Agents
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Indoles
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Phenylurea Compounds
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Sulfonamides
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Vemurafenib
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Niacinamide
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Sorafenib
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raf Kinases