The Genetics and Epigenetics in Regulation of Melanoma Progression

**3**

**Chapter 1**

**Abstract**

proposed to bypass resistance.

**2. Role of B-Raf in the cell**

**1. Introduction**

B-Raf-Mutated Melanoma

*Sarah E. Fenton, Jeffrey A. Sosman and Sunandana Chandra*

Until fairly recently, treatment options for advanced melanoma have been relatively limited. Fortunately, the last decade has seen dramatic improvements in response rates and duration of overall survival after the introduction of checkpoint inhibitors and targeted therapies against mutations in the B-isoform of Raf (B-Raf) in metastatic or inoperable melanoma. This book chapter will discuss the role of wild type B-Raf in the cell, the changes induced by mutations in this protein, and current FDA approvals for targeted therapies against B-Raf, both as a monotherapy and in combination with MEK inhibitors. We will also summarize mechanisms of resistance against these targeted therapies as well as novel therapeutic regimens

**Keywords:** melanoma, metastasis, B-Raf, MEK, targeted therapy, adjuvant

therapy was a promising strategy in the treatment of this disease [6, 10].

Wild type B-Raf is a serine/threonine-specific protein kinase that acts as an important component of the MAPK pathway regulating cellular proliferation,

Among all malignancies, melanoma is the fifth most common cancer in men and the sixth most common in women in the USA. With 91,270 new cases diagnosed in 2018 and 9320 fatalities, it has the fastest increase in incidence of any cancer worldwide [1–4]. Although the majority of cases are treated with excision, approximately 30% of patients will progress to metastatic disease [5]. On average, 60% of patients with local metastases will survive up to 5 years, while only 15% of patients with distant metastases will have similar survival rates [6]. Prior to 2011, the only approved treatment options for metastatic diseases were dacarbazine or high dose interleukin-2 (IL-2). These therapies were associated with response rates of 10–20% and rarely prolonged overall survival in the population of patients with metastatic melanoma [7–9]. Fortunately, the last decade has seen dramatic progress in melanoma treatment through the identification and targeting of mutations in the rapidly accelerated fibrosarcoma protein (Raf) that is an essential mediator of the mitogen-activated protein kinase (MAPK) pathway. First identified as an oncogene in 2002, Raf mutations have been found in melanoma, colorectal cancer, papillary thyroid carcinoma, non-small cell lung cancer, multiple myeloma, hairy cell leukemia, and specific subset of astrocytomas, to name a few malignancies [5]. Up to 50% of melanoma patients were found to carry a mutation in the B isoform of Raf (B-Raf), suggesting that targeted
