BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers

SIMPLE SUMMARY: Cutaneous melanoma represents the most aggressive form of skin cancer and its occurrence, development, and progression are based on the accumulation of several genetic alterations. BRAF mutations are frequently found in melanoma and targeted therapies against these specific genetic modifications have significantly changed the management of melanoma patients. However, these treatments are often associated with the induction of resistance. Therefore, this review aims to summarize recent findings on the impact of BRAF mutations on different aspects of melanomagenesis, including inflammation. Furthermore, we provide an overview of the main mechanisms of resistance to BRAF inhibitors and circulating tumour biomarkers. ABSTRACT: Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.