Abstract
Tumors with mutations in the gene encoding the serine-threonine protein kinase BRAF are dependent on the MAPK signaling pathway for their growth, what offers an opportunity to test oncogene-targeted therapy. Mutations at the position V600 of BRAF were described in approximately 8% of all solid tumors, including 50% of melanomas, 30 to 70% of papillary thyroid carcinomas and 5 to 8% of colorectal adenocarcinomas. Specific BRAF kinase inhibitors are undergoing rapid clinical development and promising data on efficacy have been demonstrated in activated mutant BRAF V600 melanomas. This review article will address: (a) preclinical data on the antitumor activity of BRAF inhibitors in cell lines/ in vivo models and their opposing functions as inhibitors or activators of the MAPK pathway, depending on the cellular context; (b) drug development from non-selective RAF inhibitors to selective BRAF inhibitors, such as PLX4032 and GSK2118436, with emphasis in the clinical efficacy and toxicity of these agents; and (c) possible mechanisms of resistance to BRAF inhibitors and strategies to overcome its development in BRAF mutant tumors.
MeSH terms
-
Adenocarcinoma / drug therapy*
-
Adenocarcinoma / mortality
-
Adenocarcinoma / pathology
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use*
-
Carcinoma
-
Carcinoma, Papillary
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Clinical Trials as Topic
-
Colorectal Neoplasms / drug therapy*
-
Colorectal Neoplasms / mortality
-
Colorectal Neoplasms / pathology
-
Disease Models, Animal
-
Disease-Free Survival
-
Drug Evaluation, Preclinical
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics
-
Humans
-
Indoles / chemical synthesis
-
Indoles / pharmacology
-
Indoles / therapeutic use*
-
Melanoma / drug therapy
-
Melanoma / genetics
-
Melanoma / mortality
-
Melanoma / pathology
-
Mice
-
Molecular Targeted Therapy / methods
-
Mutation
-
Phosphorylation / drug effects
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / pharmacology
-
Protein Kinase Inhibitors / therapeutic use*
-
Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
-
Proto-Oncogene Proteins B-raf* / genetics
-
Proto-Oncogene Proteins B-raf* / metabolism
-
Rats
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Sulfonamides / chemical synthesis
-
Sulfonamides / pharmacology
-
Sulfonamides / therapeutic use*
-
Thyroid Cancer, Papillary
-
Thyroid Neoplasms / drug therapy
-
Thyroid Neoplasms / mortality
-
Thyroid Neoplasms / pathology
-
Vemurafenib
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Indoles
-
Protein Kinase Inhibitors
-
Sulfonamides
-
Vemurafenib
-
BRAF protein, human
-
Proto-Oncogene Proteins B-raf