**Epigenetics in Melanoma Development and Drug Resistance Resistance**

**Epigenetics in Melanoma Development and Drug** 

DOI: 10.5772/intechopen.70983

Heinz Hammerlindl and Helmut Schaider

Heinz Hammerlindl and Helmut Schaider Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70983

#### **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.

**Keywords:** biomarker, drug resistance, histone modifications, DNA methylation, melanoma, targeted therapy

#### **1. Introduction**

The grim prognosis for metastatic melanoma patients and the steadily increasing rates of melanoma incidents, that are projected to continuously rise within the next decades [1], represent a challenge for healthcare systems worldwide and highlight the importance of developing and optimizing prevention strategies, diagnostic approaches and treatment regimes.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

After many years of research with unsatisfying treatment options and poor clinical outcomes, last decade has seen major advances in the therapy of metastatic melanoma driven by the revolutionizing discoveries of driver mutations and immune escape mechanisms that contribute to the aggressive nature of this disease. Drugs, developed to specifically exploit these mechanisms, administered either alone or in combination, have been shown to be clinically effective treatment strategies significantly increasing survival rates of patients [2–5]. Despite these recent ground-breaking advances in melanoma therapy, no currently available treatment options are curative in the majority of responding patients nor do all patients with *BRAFV600E* mutations respond to targeted therapies. Melanoma and targeted inhibition of oncogenic *BRAFV600E* became the poster child of an exciting initial therapy success followed by long-term resistance, which has also been experienced with other promising novel treatment strategies like immune checkpoint inhibitors targeting CTLA-4 and PD-1. The benefit of these new therapies is limited by the emergence of resistance, ultimately leading to tumor relapse. While the importance of genetic alterations for the development of disease and therapy resistance is unquestionable, it turns out that epigenetic remodeling is a fundamental feature of tumor development and adaption to therapy.

This chapter will briefly introduce the concept of epigenetics focusing on epigenetic alterations, especially changes in histone and DNA modifications during melanoma development and the emergence of therapy resistance. Detailed investigations into these changes will greatly contribute to our understanding of the heterogeneous and adaptive nature of melanoma. A thorough perception of how epigenetic drivers are modulating the genetic landscape will be the foundation for the development of new treatment strategies beyond pathway and immune checkpoint inhibitors.
