Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

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.

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

“…has described many of the epigenetic modifiers involved in melanoma pathogenesis, resistance to targeted and immunotherapies, and potential epigenetic targets for therapeutic adjuvants. They discuss the role of reduced 4-1BB (CD137) expression by DNA hypermethylation, HDAC6 promotion of IL-10 and PD-L1 expression, and mutations in the histone methyltransferase EZH2, which reduces expression of proteins involved in the antitumor immune response, such as RASSF5 and ITGB2 [reviewed in ( 80 )]. Recent research has expanded the association of EZH2 with immune evasion.…”

Mechanismen der Immuntherapie-Resistenz bei kutanem Melanom: Erkennen eines Formwandlers

“…Eine Übersichtsarbeit von Gracia-Hernandez et al hat viele der epigenetischen Modifikatoren beschrieben, die an der Melanompathogenese, der Resistenz gegen zielgerichtete und Immuntherapien und potenziellen epigenetischen Zielen therapeutischer Adjuvantien beteiligt sind. Sie erörtert die Rolle der reduzierten 4–1BB (CD137)-Expression durch DNA-Hypermethylierung, HDAC6-Förderung der IL-10- und PD-L1-Expression und Mutationen in der Histon-Methyltransferase EZH2, die die Expression von Proteinen reduziert, die an der Antitumor-Immunantwort beteiligt sind, wie RASSF5 und ITGB2 [80]. Jüngste Forschungen haben den Zusammenhang von EZH2 mit der Immunevasion erweitert.…”

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery

“…This prevents immune cells from reaching tumour cells and attacking them. [ 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 ]. PD-L1 is present in exosomes released from melanoma cells [ 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 ]; however, exosomes derived from metastasised melanoma cells have a higher PD-L1 content than those derived from primary focal melanoma cells.…”

“…Melanoma elicits a particularly strong immune response, and multiple immune checkpoint inhibitors have been approved by the US Food and Drug Administration for the treatment of melanoma [ 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ]. Interestingly, based on PD-L1 levels in exosomes, patients who are most likely to respond to checkpoint inhibitors can be identified and the response to these drugs can be evaluated [ 162 , 194 , 196 , 197 , 198 , 199 ].…”