Melanoma is the deadliest form of skin cancer. The disease is driven by molecular alterations in oncogenic signaling pathways, such as mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K). Activating mutations in oncogenes, such as BRAF and NRAS, and inactivating mutations in tumor suppressors genes, such as PTEN, promote this disease by altering cellular processes involved in growth, survival, and migration. Therapies targeting critical nodes in these pathways have demonstrated efficacy in clinical trials, but their therapeutic potential has been limited by the rapid onset of drug resistance. Durable therapeutic responses have also been observed in patients receiving immunotherapy. However, this activity appears to be confined to a subset of patients, and combinations with targeted therapies have raised safety concerns. Accumulating evidence strongly suggests that the pathogenesis of melanoma is also shaped by the aberrant activity of epigenetic factors that regulate gene expression through the modification of DNA and chromatin. This chapter provides a comprehensive review of the epigenetic alterations in melanoma and highlights the roles played by specific chromatin regulators during disease progression. We also discuss the clinical utility of both first and second generation epigenetic therapies in the melanoma setting, placing emphasis on the potential to overcome resistance to targeted therapies and to serve as priming agents for immunotherapies.
Part of the book: Human Skin Cancer, Potential Biomarkers and Therapeutic Targets