Abstract
Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.
Highlights
Cutaneous melanoma is the fifth most common cancer in both sexes and is less frequent, but deadlier, than other skin tumors [1]
This review focuses on epigenetics, highlighting old and new evidence regarding the role of DNA methylation and chromatin remodeling in melanoma pathogenesis and the impact of these on new treatment approaches
Many of the epigenetic drugs mentioned in this review have demonstrated safe initial signs of efficacy in melanoma patients, but several questions need to be answered: Is it possible to predict a response from epigenetic drugs by using biomarkers, as currently happens for targeted therapies? Is the timing of epigenetic drug use crucial for their efficacy? Should we think about alternative schedules of administration—i.e., on/off treatment periods, pre-planned dosage variations—to achieve the best possible result?
Summary
Cutaneous melanoma is the fifth most common cancer in both sexes and is less frequent, but deadlier, than other skin tumors [1]. Has improved the overall survival of all advanced melanoma patients, independently of genomic mutations [2]. The introduction of the association of BRAF and MEK inhibitors—two targeted therapies—in clinical practice has changed the therapeutic scenario for advanced melanoma patients harboring BRAF V600 activating mutations, which confer poorer prognoses compared to those with BRAF V600 wild-type status [3]. Patients with other molecular subtypes of melanoma have been identified over the years: 4.0/). Despite the undeniable improvement in survival rates that has come about with the use of these drugs, more than half of metastatic patients die from melanoma within. Resistance to therapy is the main reason for disease progression and, death [7]; delaying or overcoming resistance is an important clinical requirement for advanced melanoma patients. This review focuses on epigenetics, highlighting old and new evidence regarding the role of DNA methylation and chromatin remodeling in melanoma pathogenesis and the impact of these on new treatment approaches
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