Cervical cancer, driven by high-risk human papillomavirus (HR-HPV), remains a leading cause of cancer-related death. Annually, 600,000 women are diagnosed, and nearly 300,000 die from the disease. Current treatments utilize surgery and chemoradiation, which are not selective for HPV-infected cells and are less effective in advanced disease stages. These limitations highlight the need for therapies that specifically target HPV-infected cancer cells while sparing healthy cells. HPV oncogenes, E6 and E7, are the primary drivers of HPV-associated cancers. E6 promotes cancer cell survival by blocking programmed cell death. Identifying the molecular mechanisms enabling E6-mediated cell survival is essential for developing selective therapeutic strategies. Our lab developed a Drosophila model of HPV E6 oncogene expression and demonstrated that E6’s pro-survival function is evolutionarily conserved. Using this model, we identified a target in the ubiquitin-proteasome system (UPS) whose reduction disrupts the pro-survival activity of E6 and triggers cell death. We have demonstrated that the reduction of the target disrupts the pro-survival effect and leads to cell death in HPV-positive cervical cancer cells and Drosophila. These studies have the potential to provide important insights into how HPV-driven cancer cells survive and assess the target’s potential as a selective therapeutic to eliminate HPV-infected cancer cells.
