LAUSR

Simple Summary Despite major recent therapeutic advances, melanoma remains the deadliest form of skin cancer due to the capacity of melanoma cells to adapt to drug treatment and become resistant. Improved understanding of melanoma suggests that it resists treatment not just due to DNA changing mutations but also due to changes in DNA accessibility with respect to the reading and creation of different proteins. Here, we summarize the various ways in which different DNA regions become more or less open, impacting patient response to anti-cancer therapies. For instance, targeting specific proteins governing the expression of viral-like genes can alert the immune system and enhance the effects of anti-cancer therapies. Alternatively, changes in DNA accessibility allow the activation of alternative survival signals that allow melanoma cells to escape death upon treatment. Targeting factors modulating DNA accessibility in cancer cells has recently become possible through technological developments. These novel therapies, administered alone or in combination with existing ones, represent the next frontier in the treatment of advanced melanoma. Abstract 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 BRAFV600E 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.