BRAF as a target for cancer therapy

Anticancer Agents Med Chem. 2011 Mar;11(3):285-95. doi: 10.2174/187152011795347469.

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.

Publication types

  • Review

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