Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies.

Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAF V600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies.