Molecular pathways: response and resistance to BRAF and MEK inhibitors in BRAF(V600E) tumors

Clin Cancer Res. 2014 Mar 1;20(5):1074-80. doi: 10.1158/1078-0432.CCR-13-0103. Epub 2013 Dec 18.

Abstract

The RAS-RAF-MEK (MAP-ERK kinase)-ERK (extracellular signal-regulated kinase) pathway plays a central role in driving proliferation, survival, and metastasis signals in tumor cells, and the prevalence of oncogenic mutations in RAS and BRAF and upstream nodes makes this pathway the focus of significant oncology drug development efforts. This focus has been justified by the recent success of BRAF and MEK inhibitors in prolonging the lives of patients with BRAF(V600E/K)-mutant melanoma. Although it is disappointing that cures are relatively rare, this should not detract from the value of these agents to patients with cancer and the opportunity they provide in allowing us to gain a deeper understanding of drug response and resistance. These insights have already provided the basis for the evaluation of alternative dosing regimens and combination therapies in patients with melanoma.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Signal Transduction / drug effects*
  • Translational Research, Biomedical
  • Treatment Outcome

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinases