Is Knowledge About the Genetic and Epigenetic Alterations in Melanoma a Basis for Targeted Therapy?

Melanoma, a deadly form of skin cancer, showed little therapeutic progress over the past decades, with Dacarbazine being the only FDA-approved chemotherapy, offering limited efficacy. Genetic and epigenetic alterations, particularly in the MAPK and PI3K/Akt pathways, were identified as key drivers of melanoma. Over 66% of melanomas had the V600E BRAF mutation, and 15% had N-Ras mutations, leading to high MAPK pathway activity. Pharmacological inhibitors targeting these pathways were developed, showing promise in vitro but limited clinical success, suggesting the need for targeting multiple pathways simultaneously to overcome resistance. The tumor microenvironment was also recognized as a significant factor in therapeutic response, highlighting the importance of accurate tissue models for understanding melanoma mutations and improving targeted therapies.