Exploring recent advances in signaling pathways and hallmarks of uveal melanoma: a comprehensive review

Abstract

The purpose of this review was to provide a comprehensive review of the latest insights on the pathogenesis of uveal melanoma (UM) and its intracellular pathways. This article covers the epidemiology of UM, racial predispositions, cytogenetic and chromosomal alterations, gene mutations, key defective pathways, and their underlying mechanisms, as well as the application of hallmarks of cancer to UM. A key knowledge gap remains in identifying the most effective targeted therapy and determining the central pathway linking multiple signaling networks. UM is a malignant tumor arising from uveal melanocytes, predominantly affecting the choroid, with both genetic and epigenetic contributors. Key cytogenetic alterations include monosomy 3, chromosome 6p gain, chromosome 1p loss, and chromosome 8q gain. The most important UM-related signaling pathways are RAS/MAPK, PI3K/Akt/mTOR, Hippo-YAP, retinoblastoma (Rb), and p53 pathways. In the RAS/MAPK pathway, GNAQ/GNA11 mutations occur which account for more than 80% of UM cases. The PI3K/Akt/mTOR pathway promotes cyclin D1 overexpression and MDM2 upregulation, leading to p53 pathway inhibition. GNAQ/GNA11 mutations activate YAP via the Trio-RhoGTPase/RhoA/Rac1 signaling circuit in the Hippo-YAP pathway. Rb pathway dysregulation results from cyclin D1 overexpression or cyclin-dependent kinase inhibitor (CDKI) inactivation. In the p53 pathway, UM is characterized by p53 mutations, MDM2 overexpression, and Bcl-2 deregulation. Eventually, the ARF-MDM2 axis serves as a critical link between the RAS and p53 pathways. Hallmarks of cancer, such as evasion of growth suppression and self-sufficiency in growth signals, are also evident in UM. Genetic and epigenetic alterations, including NSB1, MDM2 and CCND1 amplification, and BAP1 mutations, play pivotal roles in UM pathobiology. Thus, UM exhibits a multifactorial pathology. By consolidating key mechanisms underlying UM pathogenesis, this review provides a comprehensive perspective on the involved pathways, offering insights that may facilitate the development of effective therapeutic strategies.

Keywords: Akt pathway; Hippo pathway; Uveal melanoma; hallmarks of cancer; p53 pathway; rat sarcoma virus (RAS) pathway; retinoblastoma (Rb) pathway.

Graphical abstract.

GNAQ/GNA11 mutations affect several intracellular pathways that result in tumor cell growth and uveal melanoma formation. GNA11: guanine nucleotide-binding protein subunit alpha-11; GNAQ: guanine nucleotide-binding protein G(q) subunit alpha; MAPK: mitogen-activated protein kinases; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3 kinase; RAS: rat sarcoma virus; YAP: yes-activated protein. Created in BioRender. Prakash, A. (2025) https://BioRender.com/f79v771

Figure 1

RAS/MAPK pathway role in tumor growth and cell proliferation of uveal melanoma. Cell surface receptors are stimulated and start intracellular pathways which finally result in cancerous cell proliferation. Growth factor binds to and activates membrane receptors, subsequently, a membrane-bound protein named RAS is activated. This leads to the phosphorylation (denoted by P) or activation of RAS which recruits RAF (ARAF/BRAF/CRAF) which leads to the activation of MEK1 and MEK2. Finally, ERK1 and ERK2 are activated causing tumor growth. Mutations in Gα (GNAQ/GNA11 isoforms) induce PLCβ activation which leads to persistent MAPK cascade and finally tumor growth. DAG: diacylglycerol; EGFR: epidermal growth factor receptor; GDP: guanosine diphosphate; GNA11: guanine nucleotide-binding protein subunit alpha-11; GNAQ: guanine nucleotide-binding protein G(q) subunit alpha; GPCR: G-protein coupled receptor; GRB2: growth factor receptor-bound protein 2; GTP: guanosine triphosphate; MAPK: mitogen-activated protein kinases; PKC: protein kinase C; PLC: phospholipase C; RAS: rat sarcoma virus; RTK: receptor tyrosine kinase. Created in BioRender. Prakash, A. (2025) https://BioRender.com/f79v771

Figure 2

PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway is activated by growth factors like HGF and IGF-1, promoting cell growth and tumor proliferation. GAB1: growth factor receptor-bound protein 2 associated binding protein 1; GRB2: growth factor receptor-bound protein 2; HGF: hepatocyte growth factor; IGF-1: insulin growth factor 1; IGF-1R: insulin growth factor 1 receptor; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor kappa B; PI3K: phosphoinositide 3 kinase; PTEN: phosphatase and tensin homolog; RAS: rat sarcoma virus; VEGF: vascular endothelial growth factor. Created in BioRender. Prakash, A. (2025) https://BioRender.com/f79v771

Figure 3

Hippo/YAP pathway. Hippo pathway regulates YAP by phosphorylation (denoted by P), limiting its transcriptional function. GNAQ/GNA11 mutations activate the YAP pathway, promoting cell survival and proliferation, either directly or through Hippo pathway inhibition. F-actin: filamentous actin; FAK: focal adhesion kinase; G-actin: globular actin; GNA11: guanine nucleotide-binding protein subunit alpha-11; GNAQ: guanine nucleotide-binding protein G(q) subunit alpha; GTP: guanosine triphosphate; PLCβ: phospholipase C beta; YAP: yes-activated protein. Created in BioRender. Prakash, A. (2025) https://BioRender.com/e87w713

Figure 4

p53 pathway. Mutations or disruptions in the p53 pathway can lead to genetic instability and malignancy, though TP53 mutations are rare in UM. RAS: rat sarcoma virus; UM: uveal melanoma. Created in BioRender. Prakash, A. (2025) https://BioRender.com/e87w713