Biomaterial Database

Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. 2015

Paola Queirolo, and Virginia Picasso, and Francesco Spagnolo

Department of Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.

Combined BRAF and MEK inhibition out-performed BRAF inhibitor monotherapy in 3 randomized Phase 3 studies for BRAF-mutated metastatic melanoma patients and the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib is now an FDA-approved treatment in this setting. Nevertheless, the majority of patients face progressive disease even when treated with the combination. Mechanisms of resistance to BRAF inhibition have been extensively investigated, whilst less is known about the specific mechanisms of resistance to combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors compared with BRAF inhibitor monotherapy and immunotherapy, as well as to discuss the existing evidence for the mechanisms of resistance to combined therapy and assess future treatment strategies to improve outcome based on data provided by clinical and translational research studies.

UI	MeSH Term	Description	Entries
D007093	Imidazoles	Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008545	Melanoma	A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445)	Malignant Melanoma,Malignant Melanomas,Melanoma, Malignant,Melanomas,Melanomas, Malignant
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D010091	Oximes	Compounds that contain the radical R2C	Aldoximes,Hydroxyimino Compounds,Ketoxime,Ketoximes,Oxime,Compounds, Hydroxyimino
D011728	Pyridones	Pyridine derivatives with one or more keto groups on the ring.	Pyridinones
D011744	Pyrimidinones	Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O.	Pyrimidinone,Pyrimidone,Pyrimidones
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D047428	Protein Kinase Inhibitors	Agents that inhibit PROTEIN KINASES.	Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D048493	Proto-Oncogene Proteins B-raf	A raf kinase subclass found at high levels in neuronal tissue. The B-raf Kinases are MAP kinase kinase kinases that have specificity for MAP KINASE KINASE 1 and MAP KINASE KINASE 2.	B-raf Kinase,BRAF Kinase,B-raf Kinases,BRAF Kinases,Proto-Oncogene Protein B-raf,B raf Kinase,B raf Kinases,B-raf, Proto-Oncogene Protein,B-raf, Proto-Oncogene Proteins,Kinase, B-raf,Kinase, BRAF,Protein B-raf, Proto-Oncogene,Proteins B-raf, Proto-Oncogene,Proto Oncogene Protein B raf,Proto Oncogene Proteins B raf
D020929	Mitogen-Activated Protein Kinase Kinases	A dual-specific protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.	MAP Kinase Kinases,MAPK Kinase,MAPK Kinases,MAPK-ERK Kinase,MAPK-ERK Kinases,MAPKKs,MEK,MEKs,Mitogen-Activated Protein Kinase Kinase,MAP-ERK Kinase,MAPKK,Map Kinase Kinase,Kinase Kinase, Map,Kinase Kinases, MAP,Kinase, MAP-ERK,Kinase, MAPK,Kinase, MAPK-ERK,Kinase, Map Kinase,Kinases, MAP Kinase,Kinases, MAPK,Kinases, MAPK-ERK,MAP ERK Kinase,MAPK ERK Kinase,MAPK ERK Kinases,Mitogen Activated Protein Kinase Kinase,Mitogen Activated Protein Kinase Kinases