The adenoviral E4orf4 protein: A multifunctional protein serving as a guide for treating cancer, a multifactorial disease.

Viruses exploit several cellular pathways to support their replication, and many of these virus-targeted pathways are also important for cancer growth. Consequently, studying virus-host interactions offers valuable insights into tumorigenesis and can suggest the development of novel anti-cancer therapies, with oncolytic viruses being one well-known example. The adenovirus E4orf4 protein, which disrupts several host regulatory pathways to facilitate viral infection, also functions as a potent anti-cancer agent when expressed independently. E4orf4 can selectively kill a wide range of cancer cell lines while sparing non-cancerous cells. Moreover, it effectively eliminated cancer in an in vivo Drosophila model without causing significant harm to normal tissues. In this study we provide evidence that an E4orf4-mimicking drug cocktail, comprising sublethal doses of four FDA-approved drugs targeting the pathways disrupted by E4orf4, significantly enhanced cancer cell death in many cancer cell types compared with individual drugs or less inclusive drug combinations. The quadruple drug cocktail was not toxic in non-cancerous cells. These findings provide a proof-of-principle for the potential application of virus-host interaction studies to design an effective E4orf4-based cancer therapy. Further investigation of E4orf4 interactions with the host cell will likely improve this E4orf4-based therapy by adding drugs that disrupt additional pathways. Crucially, the E4orf4-based approach offers a strategic advantage by avoiding the time-consuming development of novel drugs. Instead, it leverages existing drugs, including those that might be too toxic for use as monotherapies, by employing them at sublethal concentrations in combination. Thus, it provides a feasible and efficient method for advancing cancer therapy.