New RAF kinase inhibitors in cancer therapy.
BACKGROUND
Alterations in some key components of the MAPK pathway, such as BRAF, have been found to be related to the development of several malignancies. A number of BRAF inhibitors have been developed in recent years. Two of these compounds, vemurafenib and dabrafenib, have been licensed for the treatment of BRAF-mutant advanced melanoma.


METHODS
This article reviews the antitumour activity and safety of the BRAF inhibitors, vemurafenib and dabrafenib. Moreover, early clinical data available for the most promising new members of this family of drugs as well as the novel therapeutic strategy of dual RAF-MEK inhibition is reviewed. A perspective of the potential role of MAPK inhibition in the treatment of cancer in forthcoming years is also provided.


CONCLUSIONS
Inhibition of BRAF has achieved highly successful results in patients affected by BRAF-mutated melanoma and has revolutionised their care. Its efficacy in other malignancies is currently under evaluation in monotherapy and as combination with other agents. Early clinical results of concomitant inhibition of BRAF and MEK suggest that this therapeutic approach is superior to either BRAF or MEK inhibition alone. Identification of BRAF mutations sensitive to treatment is essential for the success of these drugs.
The Royal Marsden Hospital , Fulham Road SW3 6JJ, London , UK +44 20 7811 8576 ; +44 20 7811 8103 ; james.larkin@rmh.nhs.uk.
Juan
J
Martin-Liberal
James
J
Larkin
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
ERK; MAPK; MEK; RAF; RAS; dabrafenib; melanoma; trametinib; vemurafenib