Abstract
Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling pathways of different types of melanoma allows better characterization and provides tools for the development of therapies based on the intervention of signals promoted by these cascades. The latest World Health Organization classification acknowledged the specific genetic drivers leading to melanoma and classifies melanocytic lesions into nine distinct categories according to the associate cumulative sun damage (CSD), which correlates with the molecular alterations of tumors. The largest groups are melanomas associated with low-CSD or superficial spreading melanomas, characterized by frequent presentation of the BRAFV600 mutation. High-CSD melanomas include lentigo maligna type and desmoplastic melanomas, which often have a high mutation burden and can harbor NRAS, BRAFnon-V600E, or NF1 mutations. Non-CSD-associated melanomas encompass acral and mucosal melanomas that usually do not show BRAF, NRAS, or NF1 mutations (triple wild-type), but in a subset may have KIT or SF3B1 mutations. To improve survival, these driver alterations can be treated with targeted therapy achieving significant antitumor activity. In recent years, relevant improvement in the prognosis and survival of patients with melanoma has been achieved, since the introduction of BRAF/MEK tyrosine kinase inhibitors and immune checkpoint inhibitors. In this review, we describe the current knowledge of molecular pathways and discuss current and potential therapeutic targets in melanoma, focusing on their clinical relevance of development.
Highlights
Grade 3 or 4 treatment-related adverse events (TRAE) occurred in 79% of patients treated with the triple combination and in 73% of patients treated with only vemurafenib plus cobimetinib, so it was concluded that the addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was tolerable and significantly increased progression-free survival (PFS) in patients with BRAFV600mutant metastatic melanoma
Targeting the Mitogen-activated protein kinase (MAPK) signaling pathway has significantly improved the treatment of metastatic melanoma, with BRAF mutations being the most frequent and most important alterations to be treated
Targeted therapy for patients whose tumors harbor the BRAFV600 mutation achieves high response rates and overall survival (OS) benefit with the combination BRAF/MEK inhibition and represents the ideal first-line treatment for patients with BRAF-mutated advanced melanoma
Summary
Melanoma is the most aggressive and deadly skin cancer. Its incidence has increased steadily in the last decades, especially in the Caucasian population, posing a heightened challenge to the global healthcare system [1,2]. Relevant geographical variations exist, depending on the clinical phenotype, the genetic background of individuals, and the extent of ultraviolet (UV) radiation exposure [3]. It is one of the most frequent cancers in fair-skinned people, especially those with blond or red hair, who have light-colored eyes. The therapeutic landscape of unresectable stage III and IV melanoma has been revolutionized by immunotherapies and targeted therapies. Both strategies have shown markedly improved survival compared with the use of chemotherapy (ChT) regimens [6]. Melanoma mortality has decreased significantly since the US Food and Drug Administration (FDA) approved ipilimumab in 2011, the first immune checkpoint inhibitor (ICI) to improve survival in the advanced setting [7,8], and vemurafenib, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) tyrosine kinase inhibitor, first in class [9,10]
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