Cutaneous melanoma: From pathogenesis to therapy (Review)

Abstract

In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen‑activated protein kinase (MAPK) pathway, phosphoinositol‑3‑kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. Moreover, melanoma cells deeply interact with the tumor microenvironment and the immune system. This knowledge has led to the identification of novel therapeutic targets and treatment strategies. In this review, the epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized. The current state‑of‑the‑art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are also discussed.

Figure 1

Melanocyte malignant transformation. Physiologically, keratinocytes induces melanocyte proliferation through the production of MSH hormone and its binding with the MC1R. UV-A irradiation induces melanocytes malignant transformation through two different mechanisms: The direct transformation of normal melanocytes in neoplastic cells through the occurrence of several mutations affecting both proto-oncogene and tumor suppressor genes (TP53, NF1, PTEN, etc.). The transformation of melanocytes into benign nevi that in 80% of cases harbor the mutation BRAF^V600E. These nevi remain indolent for decades also due to immune surveillance; however, UV rays can determine the onset of additional genetic mutations, such as TERT and CDKN2A, that lead to the malignant transformation of the nevi. MSH, melanocyte-stimulating hormone; MC1R, melanocortin 1 receptor; BRAF, B-Raf proto-oncogene; CDKN2A, cyclin-dependent kinase inhibitor 2A; TERT, telomerase reverse transcriptase; ARID2, AT-rich interaction domain 2; PTEN, phosphatase and tensin homolog; NF1, neurofibromin 1; TP53, tumor protein p53; KIT, KIT proto-oncogene receptor tyrosine kinase.

Figure 2

Medical treatment of melanoma. The therapeutic approaches for the melanoma treatment are based on serine/threonine protein kinase inhibitors and the news immune checkpoint inhibitors. Dabrafenib and vemurafenib are selective RAF inhibitors; cobimetinib and trametinib are selective MEK inhibitors; ipilimumab is a monoclonal antibody IgG1k anti-CTLA-4, while nivolumab and pembrolizumab are PD-1 monoclonal antibodies IgG4 and IgG4k anti-PD-1, respectively. All these monoclonal antibodies enhance the efficacy of the immune system that is able to recognize and eradicate tumor cells. GF, growth factor; GFR, growth factor receptor; IRS1, insulin receptor substrate 1; SOS, son of sevenless; Shc, SHC adaptor protein; Grb2, growth factor receptor bound protein 2; RAS: RAS proto-oncogene GTPase; BRAF, B-Raf proto-oncogene; C-RAF: RAF-1 proto-oncogene; MAPK, mitogen-activated protein kinase; ERK, mitogen-activated protein kinase 1; MHC, major histocompatibility complex; TCR, T-cell receptor; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; APC, antigen-presenting cell; B7-1/2, CD80/CD86; CTLA-4, cytotoxic T-lymphocyte antigen 4.