Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

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.

Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by suppressing super-enhancer-driven oncogenic transcription

“…The treatment landscape for metastatic melanoma fundamentally evolved with the introduction of MAPK and immune checkpoint inhibitors, which leverage recently gained insights of certain molecular hallmarks of cancer cells 59, 11 . While these therapeutic approaches have demonstrated notable clinical benefits, their efficacy is constrained by the crucial transcriptional and cell state plasticity of melanoma cells, which gives for example rise to treatment-resistant undifferentiated cells 60, 23 . Consequently, substantial efforts are currently being invested into discovering novel therapeutics to successfully target even the rarer, stem-like cellular subpopulations.…”

“…One of the critical barriers to clinical success is intrinsic or acquired insensitivity to treatment. Various mechanisms of drug resistance have been described, with intra-tumoral heterogeneity driven by cellular phenotypic plasticity emerging as a key contributor to relapse 21, 22, 23, 24, 25 . Indeed, melanoma cells can undergo phenotype switching, transitioning between melanocytic/differentiated states governed by genes with essential roles in cell proliferation such as the lineage-specific master transcription factor MITF, and mesenchymal-like/undifferentiated states governed by the key regulators AXL and AP-1/TEAD genes, implicated in drug resistance and invasion 26, 27, 28, 29, 30, 31, 32, 33 .…”

BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers

“…The alteration in glutamine metabolism that occurs in BRAFi-treated tumours induces histone hypermethylation, promoting BRAFi resistance [ 178 ]. Extracellular signals and TME factors influence epigenetic and transcriptional programs, such as in BRAFi-treated tumours, contributing to the development of resistance to targeted therapy, both as an adaptive response or as the emergence of drug-resistant subclones [ 179 ]. BRAFi resistance can arise from changes in the activity of histone-modifying enzymes, leading to alteration of transcriptional networks resulting in resistant phenotypes.…”

“…Altered expression of some miRNAs (e.g., miR-1246, miR-4488, and miR-4443) promotes the acquisition of resistance by regulating genes involved in autophagy, whereas others (miR-204, miR-211) do so by upregulating RAS/MEK/ERK pathway [ 189 , 190 , 191 ]. Recently, BRAFi resistance has also been attributed to several lncRNAs such as SAMMSON, MIRAT, EMICERI, and LENOX (LINC00518) [ 179 , 192 ]. LncRNAs can contribute to the development of resistance through a wide range of modes of action.…”

Characterization of prognosis and immune infiltration by a novel glutamine metabolism-related model in cutaneous melanoma

“…The current primary methods of treating advanced melanoma in clinical settings involve immune checkpoint blockade, targeted therapy using v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, or a combination of these approaches (Jenkins and Fisher, 2021). Although these therapeutic strategies have significantly improved the clinical outcomes of patients with melanoma, their effectiveness can be hindered by inherent or acquired resistance that arises from the inhibitory tumor immune microenvironment and epigenetic regulators (Rubanov et al, 2022). Given the high fatality rate and poor treatment response, there is an urgent need to develop novel prognostic models for prognosis prediction and new therapeutic targets for clinical intervention.…”