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Here, we evaluate the therapeutic potential and mechanism of action of AOH1996, a first\u2010in\u2010class small molecule that targets a cancer\u2010associated isoform of proliferating cell nuclear antigen (caPCNA). Across HPV\u2010positive and HPV\u2010negative HNSCC models, AOH1996 induces robust cytotoxicity associated with mitotic arrest, multipolar mitosis, failed cytokinesis, cell\u2013cell fusion, and DNA damage. Live\u2010cell imaging reveals widespread mitotic catastrophe with limited successful mitotic progression. Notably, AOH1996 sensitivity correlates with c\u2010Myc abundance, suggesting a potential biomarker of response. In vivo, AOH1996 suppresses tumor growth with minimal toxicity in xenograft models. Together, these findings establish AOH1996 as a promising therapeutic candidate that disrupts mitotic fidelity and induces cancer\u2010selective cytotoxicity in HNSCC.<\/jats:p>","DOI":"10.1002\/jmv.71160","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:44:33Z","timestamp":1789836273000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AOH1996 Induces Mitotic Catastrophe and DNA Damage to Drive Cytotoxicity in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9675-4932","authenticated-orcid":false,"given":"Nicholas","family":"Rohlfes","sequence":"first","affiliation":[{"name":"College of Health and Human Science, Deans Office Kansas State University Manhattan Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3971-716X","authenticated-orcid":false,"given":"Nicholas A.","family":"Wallace","sequence":"additional","affiliation":[{"name":"College of Health and Human Science, Deans Office Kansas State University Manhattan Kansas 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