Multi-target drug repurposing through exploration of melanoma omics data

Summary: Backgrounds: Melanoma is an aggressive skin cancer driven by complex molecular alterations. Integrating multi-omics data can uncover potential drug targets for improved treatment strategies. Methods: Genomic and copy number altered genes were obtained from the GDC Data Portal and cBioPortal, melanoma drug-associated mutated genes from CIViCdb, differentially expressed genes(DEGs) from GEPIA2 and survival-related genes using GEPIA2, SurvNet, and HPA. Proteomic candidates are linked with melanoma staging and survival or are central in the co-expression network of TCPA, and high-abundance blood proteins are gathered from the HPA. The intersection between different omics candidates searched and those presented in at least three datasets was prioritized. Functional validation was conducted via Enrich-KG for pathway analysis, VarElect for genetic associations with melanoma, and CancerHallmarks for hallmark relevance. Drug repurposing targeted multi-gene FDA-approved drugs by enriching candidates across IDG Drug Targets, MAGMA Drugs, DGIdb, and DSigDB using Enrichr. Results: A total of 620 genomic and 789 copy number altered genes(≥10% in melanoma patients), 725 survival-associated genes, 2,148 DEGs, and 118 proteomic candidates were identified. EGFR appeared across all omics datasets, CTNNB1 and MYH11 in four, and 39 candidates in three. Pathway enrichment analysis highlighted PI3K-AKT signaling, cell proliferation and multiple cancer-related pathways. VarElect confirmed strong melanoma associations, particularly for CTNNB1 and AKT1, with CancerHallmarks enrichment linking candidates to all cancer hallmarks. Drug repurposing identified Paclitaxel, Imatinib, Sorafenib and Everolimus as the most promising FDA-approved therapies targeting multiple candidates. Conclusion: Our multi-omics approach identified key melanoma-associated genes and repurposable FDA-approved drugs. Further validations translation are needed to improve melanoma treatment. Hossein Akbarialiabad¹, Mahdi Malekpour², Fahimeh Golabi², Farzad Midjani², Ayman Grada³, Robert Judson-Torres¹, Sheri Holmen¹, Sancy Leachman¹ 1. University of Utah Health, Salt Lake City, UT, United States. 2. Shiraz University of Medical Sciences, Shiraz, Fars Province, Iran (the Islamic Republic of). 3. Case Western Reserve University, Cleveland, OH, United States. Bioinformatics, Computational Biology, and Imaging