Targeting the RAS pathway by mitogen-activated protein kinase inhibitors

Swiss Med Wkly. 2015 Dec 21:145:w14207. doi: 10.4414/smw.2015.14207. eCollection 2015.

Abstract

Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.

Publication types

  • Review

MeSH terms

  • Animals
  • Azetidines / therapeutic use
  • Benzamides / therapeutic use
  • Benzimidazoles / therapeutic use
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / therapeutic use
  • GTP Phosphohydrolases / genetics
  • Genes, ras*
  • Humans
  • Membrane Proteins / genetics
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mutation
  • Neoplasms / drug therapy*
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Piperidines / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Kinase Inhibitors / toxicity*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Pyridones / therapeutic use
  • Pyrimidinones / therapeutic use
  • Signal Transduction / drug effects*
  • Sulfonamides / therapeutic use

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • AZD 6244
  • Azetidines
  • Benzamides
  • Benzimidazoles
  • KRAS protein, human
  • Membrane Proteins
  • N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
  • N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Sulfonamides
  • Niacinamide
  • trametinib
  • Diphenylamine
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • NRAS protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • cobimetinib