Identification and Functional Validation of a Repurposed Natural Compound Against Tongue Cancer Oncogenesis and Chemoresistance

Abstract

Tongue cancer is highly aggressive and prone to relapse despite current therapies, making surgery the main treatment—often at the cost of speech and swallowing. Thus, effective drugs that reduce recurrence and chemoresistance are urgently needed. Using a drug-repurposing strategy, we integrated cancerspecific dysregulated genes with L1000CDS² to identify compounds capable of reversing oncogenic expression patterns. From the top 15 candidates, prioritized through reversal scores, reversal genes, toxicity, and prior relevance to oral cancers, we identified a natural product with a cosine distance of 1.51 that reverses 77 genes, including several linked to chemoresistance. In vitro and ex vivo assays validated its anticancer activity and revealed a previously unknown target in oral cancer. This compound shows strong potential to treat oral malignancies while minimizing chemoresistance and relapse, and further investigations are underway.