AI-Driven Drug Target Screening Platform Identified Oncogene CACNA2D1 Activated by Enhancer Infestation in Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma

The management of nasopharyngeal cancer (NPC) is rapidly evolving, with immune checkpoint inhibitors emerging as a prominent treatment approach. However, drug development targeting specific molecular and cellular abnormalities in NPC has slowed. Recent advancements in artificial intelligence (AI) and bioinformatics, particularly those integrating multi-omics data, offer a more effective alternative to traditional in vitro screening methods for identifying clinically actionable targets in NPC. Through a combination of multi-omics analyses and AI-driven screening, we identified CACNA2D1 as a novel cancer-cell-specific therapeutic target in NPC. Our research indicates that exploiting Epstein-Barr virus (EBV) tethering increases H3K27 acetylation near the <i>CACNA2D1</i> promoter. Analysis of clinical specimens revealed significant upregulation of CACNA2D1 at both the transcriptional and translational levels (<i>p</i>-value < 0.01). Functional studies demonstrated that the mouse tumour size shrank by one-third upon the depletion of CACNA2D1, and there was an 85% reduction in cancer cell growth through the blockage of enhancers, while the presence of CACNA2D1 conferred a survival advantage during NPC tumour development. These findings highlight the potential of CACNA2D1 as a promising target for therapeutic intervention in NPC.