Roles and mechanisms of aberrant alternative splicing in melanoma — implications for targeted therapy and immunotherapy resistance

Abstract

Background Despite advances in therapeutic strategies, resistance to immunotherapy and the off-target effects of targeted therapy have significantly weakened the benefits for patients with melanoma. Main body Alternative splicing plays a crucial role in transcriptional reprogramming during melanoma development. In particular, aberrant alternative splicing is involved in the efficacy of immunotherapy, targeted therapy, and melanoma metastasis. Abnormal expression of splicing factors and variants may serve as biomarkers or therapeutic targets for the diagnosis and prognosis of melanoma. Therefore, comprehensively integrating their roles and related mechanisms is essential. This review provides the first detailed summary of the splicing process in melanoma and the changes occurring in this pathway. Conclusion The focus of this review is to provide strategies for developing novel diagnostic biomarkers and summarize their potential to alter resistance to targeted therapies and immunotherapy.

From bedside to genetic analysis: New insights into pathophysiology of melanoma, basal cell carcinoma, and other cancers

“…The authors of this review article also emphasized that abnormal RNA splicing is a key factor in the pathophysiology of essentially all malignancies. 11 This data collaborates with research done by Munoz and co-authors that UV radiation produces an alternative DNA splicing. 12 Munoz and co-authors also briefly mention in their manuscript, published in 2009, that alternative splicing appears to play a role in cancer pathogenesis.…”

“…In 2020, the authors published a review article on the role of the WNT signaling pathway in developing melanoma 10 (Mueller mechanism). In March 2024, other investigators reported in their review article the pivotal role of abnormal splicing in the development and pathogenesis of melanoma 11 (Zemtsov mechanism). The authors of this review article also emphasized that abnormal RNA splicing is a key factor in the pathophysiology of essentially all malignancies.…”

“… 12 This author decided to combine Mueller and Zemtsov mechanisms. Furthermore, reading carefully the article cited above, 11 one mechanism for activation of BRAF oncogene in MAP kinase pathway is a point mutation in intron 8 (which leads to exons 4–8 not being translated). 11 An extensive literature search revealed that UV radiation can induce a variety of point mutations.…”

“…Furthermore, reading carefully the article cited above, 11 one mechanism for activation of BRAF oncogene in MAP kinase pathway is a point mutation in intron 8 (which leads to exons 4–8 not being translated). 11 An extensive literature search revealed that UV radiation can induce a variety of point mutations. 13 Obviously, DNA exposure causes the formation of a variety of abnormal DNA structures such as cyclobutane pyrimidine dimers (CPD), 6‐4 pyrimidine pyrimidone, and its Dewar isomers.…”

A Proteomics Approach Identifies RREB1 as a Crucial Molecular Target of Imidazo–Pyrazole Treatment in SKMEL-28 Melanoma Cells

“…Other coherent results from our analysis of biological and molecular processes strongly involved in melanoma are RNA processing, phosphorylation mechanisms, lysosomal system involvement [ 35 ], cellular response to growth factor beta receptor signaling, and epithelial cell migration. Interestingly, it was observed that FGF-2 can promote angiogenesis by acting together with VEGF since FGF is a key regulator for the development of blood and lymphatic vessels, as it modulates endothelial metabolism driven by MYC-dependent glycolysis.…”