title: [Dabrafenib: the new inhibitor of hyperactive B-RAF kinase].
abstract: The B-RAF kinase is among major targets of biological therapy of cancer. B-RAF acts in the MAP kinase pathway, being activated by any of the RAS G-proteins. Hyperactive B-RAF is typically detected in chemoresistant and radioresistant malignant metastatic melanoma. In this study, we focus on the reversible ATP-competitive inhibitor dabrafenib (GSK-2118436), which is now in phase III clinical trial for use in subjects with various cancers expressing hyperactive B-RAF. Dabrafenib is selective for B-RAFV600E and B-RAFV600K (less for B-RAFV600D) over wild-type B-RAF. Thus, similarly to vemurafenib (Zelboraf), suggested is mandatory pre-screening for activating B-RAF mutations in the cancer tissue of each subject. Dabrafenib inhibits neoplastic growth at concentrations 53.8 nM in plasma, which corresponds to 30 mg/kg qd p.o., or to --- 3 mg/kg qd i.v. Most of the cancers expressing hyperactive B-RAF respond to dabrafenib treatment, but the complete response is only rarely achieved. Toxic side effects include skin lesions, pyrexia, frequent fatigue, nausea and pain. Resistance to dabrafenib is frequently developed via de novo RAS mutations, leading to the disease relapse. The RAS G-protein is capable of signaling downstream not only through B-RAF, but also through closely related C-RAF, which circumvents the effects of the B-RAF inhibitor. Thus, dabrafenib should not be prescribed to subjects with neoplasias that are positive for activating RAS mutations. Since B-RAF mutations alone cause only the formation of benign naevi, since the tumors frequently and quickly acquire resistance to B-RAF inhibitors, and because the B-RAF-inhibitor-mediated treatment outcomes are severely affected by changes in the activity and expression of a number of signaling molecules (among them PI3K/mTOR, PTEN, AKT, MEK, PDGFRβ), it can be anticipated that dabrafenib treatment should be suggested only as a part of combined therapy targeting simultaneously the other pathways responsible for cancer onset and progression.
authors.affiliation: petr.heneberg@if3.cuni.cz
authors.forename: P
authors.initials: P
authors.lastname: Heneberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001691:Biological Therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy; D009154:Mutation; D010091:Oximes / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib