Molecular Markers and Targets in Melanoma

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.

The Anticancer Potential of Doxycycline and Minocycline—A Comparative Study on Amelanotic Melanoma Cell Lines

“…The malignant transformation of melanocytes can be triggered by different environmental factors, including UV radiation, heavy metals, or pesticides. Moreover, geographical location, skin phototypes I and II, intermittent and intense sun exposure, numerous pigment nevi, genetic susceptibility, or immunosuppression also belong to risk factors for melanoma development [ 5 , 6 ]. The process of melanocyte transformation to melanoma cells is based on genetic and epigenetic changes.…”

Oxidative-Stress-Sensitive microRNAs in UV-Promoted Development of Melanoma

“…Of note, the mutation frequency rate in melanoma is higher than that described for most other cancers. In this context, strong evidence indicates that UV-induced DNA lesions represent a major causative factor for mutations in melanoma-relevant genes [8][9][10][11][12]. Typical and atypical UV mutation signatures can be related to the direct absorption of UV energy with the formation of secondary photoproducts, as well as consequent to UV-generated ROS able to oxidize nucleotide bases [38][39][40][41][42].…”

“…Several signaling pathways have been associated with abnormal proliferation, growth, survival, migratory, and invasive properties of neoplastic melanocytes. In particular, among the underlying molecular aberrations characterizing melanoma and its etiology, the most frequent molecular changes involve genetic mutations of CDKN2A, CCND1, CDK4, MITF, c-KIT and MC1R genes; dysregulation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-Akt pathways; aberrant p53, STAT3, NRF2, NFκB, cadherin, and Wnt signaling pathways; and epigenetic alterations [8][9][10][11][12]. Ultimately, a complex and intricate connection between these aberrant signaling pathways and genetic abnormalities leads to a cascade of molecular events promoting uncontrolled melanocyte growth, proliferation, differentiation, migration and greater cell survival, resistance to apoptosis, invasion, and metastasis, which collectively promote tumorigenesis [8][9][10][11][12].…”

Functionalization of Nanomaterials for Skin Cancer Theranostics

“…Because of the restrictive method including numerous medications, a novel technique for treating melanoma is desperately required ( Bowman et al, 2021 ; Millán-Esteban et al, 2021 ; Teixido et al, 2021 ).…”