Advances in Melanoma: From Genetic Insights to Therapeutic Innovations

Abstract

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

Keywords: MAPK pathway; PI3K/Akt/mTOR pathway; epigenetic modifications; genetic mutations; immune checkpoint inhibitors; immunotherapy; mRNA vaccines; melanoma; tumor microenvironment.

Figure 1

MAPK/MEK/ERK and PI3K/Akt/mTOR Signaling Pathways. (a) The binding of epidermal growth factor (EGF) to its receptor (EGFR) on the cell membrane leads to the activation of Ras by facilitating the exchange of GDP for GTP. Activated Ras (Ras-GTP) interacts with and activates BRAF, which, in turn, phosphorylates and activates MEK. Subsequently, MEK phosphorylates and activates ERK. Phosphorylated ERK translocates to the nucleus, where it interacts with transcription factors such as c-Fos, c-Jun, ELK-1, AP1, CREB, and STAT1, causing changes in gene expression that promote cell proliferation, differentiation, and survival. (b) The same activated EGFR recruits and activates PI3K. Activated PI3K converts PIP2 (phosphatidylinositol 4,5-bisphosphate) into PIP3 (phosphatidylinositol 3,4,5-trisphosphate) at the inner leaflet of the plasma membrane; this reaction can be regulated by PTEN, which dephosphorylates PIP3. PIP3 recruits Akt to the membrane, where it is phosphorylated and activated by PDK1 (3-phosphoinositide-dependent protein kinase-1) and mTORC2 (mechanistic target of rapamycin complex 2). Activated Akt leads to the activation of mTORC1. Activated mTORC1 promotes protein synthesis, cell growth, and survival. Created with BioRender.com.

Figure 2

Epigenetic Modifications. The diagram shows some of the epigenetic modifications that occur in the genome as part of gene expression regulation. (a) Histone Modifications: methylations and demethylations carried out by histone methyltransferases and histone demethylases, respectively, and acetylations and deacetylations conducted by histone acetyltransferases and histone deacetylases, respectively. (b) DNA Methylation: DNA methyltransferases and DNA demethylases can add methyl groups to or remove from cytosines in DNA (particularly in CpG islands) to silence or activate gene expression. (c) Non-Coding RNAs: the regulation of mRNAs mediated by lncRNAs and miRNAs, which can bind complementarily to mRNA and lead to its inhibition or degradation. Created with BioRender.com.

Figure 3

Illustration of Immune Checkpoint Pathways and their Role in Immunotherapy. The left panel shows the positive costimulation of T cells through the interaction of CD28 with B7 while simultaneously inhibiting the action of CTLA-4 thanks to blocking by ipilimumab. The right panel demonstrates the inhibition of negative costimulation by immune checkpoint inhibitors, such as pembrolizumab and ipilimumab, which block both PD-1 and PD-L1, leading to the enhanced cytotoxic effects of T cells against tumor cells. Created with BioRender.com.

Figure 4

mRNA Vaccines. (a) Immune response against tumor cells: Macrophages are capable of phagocytosing and processing cells and molecules from the tumor niche to present antigens to T lymphocytes. These T cells identify the antigen presented on the surface of cancer cells and eliminate them. However, tumor cells carrying somatic mutations can produce neoantigens, thereby decreasing the efficiency of antigen recognition and the immune response. (b) Overview of the mechanism of mRNA vaccines targeting, melanoma: The process begins with the extraction of specific tumor antigens, which are then encoded into mRNA. The mRNA is encapsulated and administered to the patient, leading to the production of neoantigens by antigen-presenting cells (APCs). This stimulates an immune response, enhancing the cytotoxic activity of T cells against melanoma cells. Created with BioRender.com.