Melanoma Cell Signalling: Looking Beyond RAS-RAF-MEK

Abstract

Melanoma is an invasive and malignant form of skin cancer (Besaratinia and Pfeifer, 2008). It originates from melanocytes, which reside in the epidermal layer of the skin. Besides the skin, melanoma’s rapidly proliferative and aggressive nature leads to its manifestation in internal organs such as brain, lung and liver (Franco-Lie et al., 2011; Lejeune et al., 1992). Ultraviolet (UV) radiation (sunlight or tanning beds) is the main carcinogen involved in melanoma development. However, the type (UVA versus UVB) and duration of UV radiation (intermittent versus chronic and childhood sun exposure) necessary for melanoma initiation remains ambiguous (Algazi et al., 2010; Besaratinia and Pfeifer, 2008; Lazovich et al., 2010; Walker, 2008). In addition, the presence of melanocytic nevi and hereditary genetic mutations predisposes individuals to melanoma (Navarini et al., 2010; Pho and Leachman, 2010; Whiteman et al., 2003). As a result of these factors, it is estimated that 132,000 melanoma skin cancers occur annually (World Health Organization [WHO], 2011). This value is set to rise by 4,500 incidences for every 10% decrease in the UV-protective ozone levels (WHO, 2011). Prevention strategies designed to curtail the onset of melanoma and improved treatment for this evolving anomaly require urgent action. Current treatments and adjuvant therapies for melanoma includes, surgical excision, radio-, chemoand immunotherapy (Dummer et al., 2010; Petrescu et al., 2010). However, with the recurrence of these melanomas, the spotlight is on molecular targeted therapy. Such therapies require an in depth knowledge of melanoma signalling to treat this cancer. Molecular targeted therapy has focused predominantly on the RAS-RAF-MEK [mitogen activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase] and phosphoinositide-3-kinase (PI3K)/AKT pathways (Algazi et al., 2010; Friedlander and Hodi, 2010; Held et al., 2011; Sullivan and Atkins, 2010). However, due to the complex network of signalling pathways, it has become evident that targeting single pathways to eradicate melanoma is insufficient (Table 1) (Jiang et al., 2011; Johannessen et al., 2010; Nazarian et al., 2010; Shields et al., 2007). Shields et al. (2007) found a distinct subset of melanoma cell lines that did not exhibit high ERK and AKT activation but had increased expression of epithelial markers like P-cadherin, E-cadherin and CD24. These epithelial-like melanoma also had a loss of p53 function, decreased microphthalmia-associated transcription factor (MITF) levels and its targeted gene expression. Recent studies have also shown that many subsets of melanoma cells exhibit resistance to B-RAF inhibitors (Jiang et al., 2011; Nazarian et al., 2010).