Abstract
Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
Highlights
Melanoma is the most common and aggressive form of skin cancer which develops from the uncontrolled growth of melanocytes
Melanomas are commonly found on the trunk and face of male patients and the arms and lower legs of female patients but have the potential to develop on all parts of the body, those exposed to UV radiation from the sun [4,6]
Metabolic rewiring is an established hallmark of cancer, and BRAF mutant melanoma cells exhibit a high level of glycolytic activity [34,71]
Summary
Melanoma is the most common and aggressive form of skin cancer which develops from the uncontrolled growth of melanocytes. Risk factors for the development of melanoma include exposure to UV radiation, phenotypic traits such as fair skin, hair and eye colour, geographical location and a high number of benign nevi [7,8]. NRAS mutations (most commonly in codon 61 and in codon 12 and 13) result in the constitutive activation of PI3K and MAPK pathways, promoting cell proliferation, differentiation and tumorigenesis [3]. NF1 inhibits MAPK signalling and so in melanomas with a loss of function mutation in NF1, uncontrolled MAPK pathway activity can lead to tumorigenesis. UV radiation can stimulate hyperactive MAPK signalling and lead to tumorigenesis [19]
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