Repurposing FDA-approved drugs targeting signature genes associated with cancer of unknown primary: an orphanoinformatics approach

Vollständiger Abstract

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Abstract Background Cancer of unknown primary (CUP) is a rare and aggressive metastatic cancer characterized by an undefined primary site of tumor origin with poor overall survival (favorable group: 10–16 months and unfavorable group: 6–7 months). Thus, the current study aimed to identify and repurpose a drug targeting the signature gene involved in CUP pathogenesis. Methods The relevant dataset for CUP was identified from the GEO database using a systematic search. Oncogene and tumor suppressor genes in CUP were used to identify protein-protein interactions and perform enrichment analysis in STRING. The hub and signature genes involved in CUP were identified using the CytoHubba plugin of Cytoscape 3.10.4. The drug candidates for signature genes were retrieved from GeneCards ® and DGIdb database which were docked to repurpose FDA-approved drugs against the signature target involved in CUP. Results Out of 4815 genes expressed in CUP, 2670 were upregulated, and 913 were downregulated, of which 144 were oncogenes, and 80 were tumor suppressor genes, respectively. 1039 Gene Ontology terms and 141 KEGG pathways were significantly enriched in the protein-protein interaction network. A total of 43 genes were identified as hub genes involved in CUP, of which 9 ( STAT3/KRAS/NRAS/CTNNB1/TGFB1/JUN/FOS/ERBB2/BCL2 ) were considered signature genes. Dactinomycin, along with Sacituzumab-govitecan, Venetoclax, Dabrafenib, and Sorafenib, showed the highest binding affinity with signature genes. Conclusion Dactinomycin emerged as the most promising candidate, targeting multiple signature genes (TGFB1, BCL2, STAT3, JUN, and FOS) involved in CUP pathogenesis and exhibiting the highest binding affinity.