Targeting mutant BRAF in melanoma: current status and future development of combination therapy strategies

Cancer J. Mar-Apr 2012;18(2):124-31. doi: 10.1097/PPO.0b013e31824b436e.

Abstract

The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. In this commentary, we review the latest research delineating the role of mutant BRAF in melanoma initiation and progression and discuss the remarkable 10-year journey leading up to the recent U.S. Food and Drug Administration approval of the small-molecule BRAF inhibitor vemurafenib. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. It is hoped that our evolving understanding of melanoma genetics and intracellular signaling coupled with a growing armamentarium of signal transduction inhibitors will lead to significant improvements in the level and durability of therapeutic response in metastatic melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Mutation*
  • Protein Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf