Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

SIMPLE SUMMARY: Melanoma affects over 300,000 people worldwide every year. Recent advancements in therapeutic treatments for melanoma patients, such as targeted therapies and immunotherapy, have improved the survival of patients without advanced disease. However, an important subset of patients remains refractory or develops resistance. Melanomagenesis, disease progression, and resistance to therapies are epigenetically regulated processes. Emerging preclinical and clinical research elucidates the mechanisms by which epigenetic drugs can prevent resistance or enhance the therapeutic efficacy of the aforementioned therapies in addition to chemotherapy, radiation therapy, and others. In this review, we assess the role of epigenetics in melanoma progression and resistance to targeted and immune therapies. Additionally, we discuss recent preclinical and clinical reports evaluating the use of epigenetic drugs as adjuvants to enhance the current therapeutic approaches for melanoma patients. ABSTRACT: Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.