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Introduction
Malignant melanoma (MM) is a highly malignant type of cancer characterized by aggressive behavior and rapid metastasis to distant sites. Existing melanoma treatments include surgical resection, chemotherapy and radiotherapy (1). Despite notable advancements in immunotherapy, targeted agents and oncolytic viral therapy, the 5-year survival rate is 50% for patients with advanced melanoma (2). Therefore, there is a critical need to investigate novel therapeutic targets for the treatment of MM.
Melanoma is commonly associated with mutations in the Ser/Thr kinase BRAF (50%), the small GTPase NRAS (25%) or the RAS regulator neurofibromin 1 (14%), leading to enhanced RAS/MAPK signaling (3). This pathway, involving RAS, RAF, MEK and ERK, serves crucial roles in melanoma, thus indicating that it may be a prominent therapeutic target of significant interest (4). MEK serves as a key relay in the pathway, passing signals from RAF to ERK. Pharmacological inhibition of MEK can disrupt this signaling relay, thereby impeding ERK activation and effectively arresting the aberrant signaling cascade that fuels cancer proliferation (5). Notably, preclinical and clinical studies have highlighted the RAS/RAF/MAPK pathway as a key therapeutic target, particularly in the era of precision medicine (1–3,6).
Wnt/β-catenin signaling, which regulates cell proliferation, is frequently hyperactive in cancer, including melanoma (7). In the canonical β-catenin-dependent pathway, Wnt ligands bind to Frizzled receptors on the cell surface, triggering Dishevelled (DVL) recruitment and disruption of the β-catenin destruction complex (8), its translocation into the nucleus and subsequent alteration of gene expression, particularly affecting TCF/LEF target genes. In cancer, this signaling cascade upregulates genes such as cyclin D1 and cMyc, driving G1/S cell cycle progression, and promoting tumor growth and malignancy (7). The involvement of Wnt signaling in melanoma pathogenesis remains a topic of ongoing discussion, with its precise contributions subject to debate (7,9). Numerous studies have demonstrated that Wnt/β-catenin signaling serves a role in facilitating tumor initiation and progression in melanomas harboring mutations in BRAF and NRAS (10–12). A previous study using an engineered mouse model also linked Wnt signaling to the transformation of melanocyte stem cells into melanoma in BRAF and PTEN mutants (13). Notably, it has been observed that the efficacy of BRAF inhibition is enhanced in scenarios where β-catenin levels are decreased (14).
Pleckstrin homology domain-containing family A member...