Epigenetics in Melanoma Development and Drug Resistance

Abstract

Melanomas, which originate from melanocytic cells, mainly develop in the skin but can also arise at other body sites. The disease accounts for approximately 90% of deaths related to cutaneous tumors with late stage metastatic melanoma having a very poor prognosis of 6-9 month median survival for untreated patients. Research in the last decades resulted in ground-breaking discoveries of melanoma genetics and biology. High frequency mutations in genes like BRAF, NRAS and KIT, which lead to hyper-activation of the MAPK signaling pathway, drive melanoma progression. Targeting the MAPK signaling pathway has successfully been translated into effective therapies that significantly improve patient survival. Despite the unquestionable importance of such genetic events, the involvement of epigenetic alterations for melanoma development, and resistance to aforementioned therapies is becoming increasingly apparent. In this chapter, epigenetic alterations commonly found in melanoma are introduced, with a focus on histone and DNA modifications and their relevance for melanoma development, progression and therapy response. Detailed knowledge about this emerging aspect of melanoma research will help to understand the plastic nature of melanoma and set the foundation for novel treatment strategies that target aberrant gene regulation on genetic and epigenetic levels.

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

“…The acetylation (ac) of histone lysines (K), is associated with the transition to an “open” conformation; this weakens DNA–histone interactions, increases DNA accessibility, and facilitates transcription. Acetylated lysine residues may also serve as binding platforms for transcription factors and other histone-modifying enzymes, such as bromodomains [ 59 ]. Another type of histone modification is methylation (me) of lysine and arginine (R) residues.…”

“…One of the clinical observations that have postulated the link between epigenetic regulation and resistance to cancer therapy is the so-called “drug holiday” concept, which refers to intermittent treatment programs or treatment breaks. This strategy is often applied to delay the onset of resistance to therapy but is not potent on a genetically resistant phenotype [ 59 ]. Particularly for CM, it was observed that rechallenging patients with BRAFi after a free period of treatment and tumor progression resulted in a significant clinical response upon BRAFi and BRAF + MEKi treatments [ 161 ].…”

“…To date, the proposed mechanisms for CM resistance to immunotherapy are downregulation of MHC molecules, loss of antigenic expression, T-cell exhaustion, aberrant expression of PD-L1 in response to IFN-γ production by T cells, along with the altered expression of chemokines such as CCL3, CXCL1, and CCL4 [ 9 ]. Although it is well known that epigenetic regulation has critical roles in shaping the identity and differentiation of immune cells, the administration of epigenetic therapy should be done with caution in immunotherapy-resistant CMs, as these agents can affect other cells within TME in addition to tumor cells [ 59 ].…”

The tumor genetics of acral melanoma: What should a dermatologist know?

“…This ecosystem includes epigenetics, proteomics, metabolomics, the tumor microenvironment, and the host's immunologic response, germline mutations, and even microbiome. 4,12,15,31,67,[93][94][95][96][97][98][99][100][101][102] Of particular importance are immunology and germline mutations. A critical step in melanoma development is the ability of the tumor to evade detection by the immune system.…”

“…This ecosystem includes epigenetics, proteomics, metabolomics, the tumor microenvironment, and the host's immunologic response, germline mutations, and even microbiome. 4 , 12 , 15 , 31 , 67 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 Of particular importance are immunology and germline mutations.…”