title: Mechanism and consequences of RAF kinase activation by small-molecule inhibitors.
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.
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Research, University of California San Francisco, San Francisco, CA 94143-0128, USA.
authors.forename: M
authors.initials: M
authors.lastname: Holderfield
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94523, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Nagel
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94523, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Stuart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D055503:Protein Multimerization / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000077484:Vemurafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010671:Phenylurea Compounds; D013449:Sulfonamides; D000077484:Vemurafenib; D009536:Niacinamide; D000077157:Sorafenib; D048490:raf Kinases