Current Insights into the Role of BRAF Inhibitors in Treatment of Melanoma

Melanomas represent only 4% of all skin cancers, but their mortality rate is more than 50 % of any other skin cancer. Alteration in genetic and environmental factors are the risk factors for melanoma development. The RAS/RAF/MEK/ERK or Mitogen-activated protein kinase (MAPK) pathway is activated in melanoma. BRAF activation is necessary to govern differentiation, proliferation, and survival. Mutations in BRAF were found in 80-90% of all melanomas. Over 90% of BRAF mutations occur at codon 600, and over 90% of them are BRAFV600E other common mutations are BRAFV600K, BRAFV600R, BRAF V600'E2', and BRAF V600D. Based on alpha C-helix and DFG motif (alpha C-helix-IN/DFG-IN), (alpha C-helix-IN/DFG-OUT), (alpha C-helix-OUT/DFG-IN) and (alpha C-helix-OUT/ DFG-OUT) are four structural types of inhibitors for targeting BRAF. Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib are FDA-approved for the treatment of BRAF. Understanding melanoma pathogenesis, RAS/RAF/MEK/ERK or MAPK pathway, and BRAF conformations, mutations, the problems with FDA approved BRAF inhibitors will be important for new drug discovery, modification of existing BRAF barriers to improve target specific action, and prevent increasing response levels while minimizing toxicity.

Automated summary

Melanomas, accounting for only 4% of skin cancers, have a mortality rate higher than 50% of other skin cancers. Genetic and environmental alterations are risk factors for melanoma development. The RAS/RAF/MEK/ERK or MAPK pathway is activated in melanoma, with BRAF mutations found in 80-90% of cases. Understanding melanoma pathogenesis, BRAF conformations, and the problems with current FDA-approved inhibitors is crucial for new drug discovery and improving treatment effectiveness.