BRAF Gene and Melanoma: Back to the Future

Int J Mol Sci. 2021 Mar 27;22(7):3474. doi: 10.3390/ijms22073474.


As widely acknowledged, 40-50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS-RAF-MEK-ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

Keywords: BRAF mutation; immunotherapy; melanoma; targeted therapy.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Cell Cycle
  • Chemotherapy, Adjuvant
  • Clinical Trials as Topic
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Immunohistochemistry
  • Immunotherapy
  • MAP Kinase Signaling System
  • Male
  • Medical Oncology / trends
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local / drug therapy
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / physiology*
  • Recurrence
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases