Braf-Mutant Melanomas: Biology and Therapy

Abstract

The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in 40-50% of melanomas and its role in melanoma development is paramount. BRAF mutations confer constitutive activation of MAPK signalling. The large majority (about 90%) of BRAF mutations occur at amino acid 600; the majority are BRAF^V600E mutations and less frequently BRAF^{v600K, V600D} and ^V600M. The introduction of drugs that directly target BRAF-mutant protein (BRAF inhibitors) and of agents that stimulate immune response through targeting of immune check inhibitor consistently improved the survival of melanoma BRAF^V600-mutant patients with unresectable/metastatic disease. In parallel, studies in melanoma stage II-III patients with resectable disease have shown that adjuvant therapy with ICIs and/or targeted therapy improves PFS and RFS, but not OS compared to placebo; however, neoadjuvant therapy plus adjuvant therapy improved therapeutic response compared to adjuvant therapy alone.

Keywords: BRAF mutations; MAPK; genomic profiling; immunotherapy; melanoma; skin tumors; targeted therapy; tumor evolution.

Figure 1

Schematic representation of the structure of BRAF protein. BRAF protein is composed of 766 amino acids. Several functionally relevant structural regions are identified: BSR (BRAF-specific region); CR1 (Constant Region 1) containing two domains, RBD (Ras-binding domain) and CRD (Cystein-Rich Domain); CR2 (Constant Region 2); CR3 containing the kinase domain. Within the kinase domain, the activation loop is outlined with the most frequent missense mutations observed in melanomas.