Targeting Cancer-Associated PCNA with AOH1996 Induces Mitotic Catastrophe and Enhances Cisplatin Therapy in Cervical Cancer

Cervical cancers (CaCx) remain a significant health burden. Limitations on CaCx chemotherapeutic intervention caused by toxic side effects are a persistent barrier to care. Here, we show that the human papillomavirus oncogenes that cause most CaCx also increase the levels of a cancer-associated isoform of PCNA known as caPCNA. The abundance of caPCNA is specifically elevated in CaCx. Similar to observations in other cancers, we found that a small molecule inhibitor of caPCNA (AOH1996) selectively killed cell line, organoid, and xenograft models of CaCx. Our subsequent molecular analysis identified a novel ability of AOH1996 to induce cell death by disrupting the interaction between PCNA and gamma tubulin, resulting in mitotic arrest. We show AOH1996 selectively induces mitotic death in transformed cells, because these cells attempt to progress through mitosis, rather than decondensing their chromosomes and reforming their nuclear membranes like untransformed control cells. Further, we show that these differences allow AOH1996 to specifically sensitize CaCx cells to cisplatin, a frontline chemotherapeutic used to treat CaCx. We found that subtherapeutic doses of AOH1996 and cisplatin could reduce CaCx xenograft growth and improve survival, similarly to a therapeutic dose of cisplatin without the cisplatin-induced toxicity that restricts care. To our knowledge, this study provides the first evidence that AOH1996 can function as a cisplatin-sensitizing agent in cervical cancer models.