Abstract
Skin cutaneous melanoma (SKCM) remains a formidable clinical challenge due to frequent therapeutic resistance. This study employs a multi-omics and computational approach to characterize the pivotal role of aberrant alternative splicing (AS), regulated by the splicing factor (SF)-kinase axis, in melanoma pathogenesis and to identify novel drug repurposing opportunities. Analysis of TCGA and GTEx data revealed significant overexpression of key serine/arginine-rich splicing factors, SRSF1 and SRSF2, in SKCM tumors. Subsequent profiling of AS landscapes identified widespread, high-frequency splicing alterations, including constitutive exon skipping (e.g., 100% skipping of exons 2.2-3.4) and intron retention events, indicating a systematic "oncogenic splicing switch." Functional enrichment and protein-protein interaction network analyses confirmed the central role of these SFs within spliceosome and mRNA processing pathways. Given the difficulty of directly inhibiting SFs, we investigated their upstream regulators. We identified a network of druggable kinases including SRPK1, CLK1/2, and CDK12 that phosphorylate and control SRSF1 activity. Molecular docking of known kinase inhibitors demonstrated high binding affinity for these targets, with THZ531 (CDK12), SRPIN340 (SRPK1), and TG003 (CLK1) emerging as promising repurposing candidates. In conclusion, this study delineates a dysregulated SF-kinase axis driving profound splicing reprogramming in melanoma. It proposes a novel therapeutic strategy of indirectly modulating oncogenic alternative splicing by targeting these upstream regulatory kinases using existing inhibitors, offering a rapid and actionable pathway for overcoming resistance in precision dermatology