Inhibition of human-HPV hybrid ecDNA enhancers reduces oncogene expression and tumor growth in oropharyngeal cancer

Takuya Nakagawa (), Jens Luebeck, Kaiyuan Zhu, Joshua T. Lange, Roman Sasik, Chad Phillips, Sayed Sadat, Sara Javadzadeh, Qian Yang, Abdula Monther, Santiago Fassardi, Allen Wang, Kersi Pestonjamasp, Brin Rosenthal, Kathleen M. Fisch, Paul Mischel, Vineet Bafna and Joseph A. Califano ()
Additional contact information
Takuya Nakagawa: San Diego
Jens Luebeck: UC San Diego
Kaiyuan Zhu: UC San Diego
Joshua T. Lange: Stanford University School of Medicine
Roman Sasik: San Diego
Chad Phillips: San Diego
Sayed Sadat: San Diego
Sara Javadzadeh: UC San Diego
Qian Yang: San Diego
Abdula Monther: San Diego
Santiago Fassardi: San Diego
Allen Wang: San Diego
Kersi Pestonjamasp: San Diego
Brin Rosenthal: San Diego
Kathleen M. Fisch: San Diego
Paul Mischel: Stanford University School of Medicine
Vineet Bafna: UC San Diego
Joseph A. Califano: San Diego

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Extrachromosomal circular DNA (ecDNA) has been found in most types of human cancers, and ecDNA incorporating viral genomes has recently been described, specifically in human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC). However, the molecular mechanisms of human-viral hybrid ecDNA (hybrid ecDNA) for carcinogenesis remains elusive. We characterize the epigenetic status of hybrid ecDNA using HPVOPC cell lines and patient-derived tumor xenografts, identifying HPV oncogenes E6/E7 in hybrid ecDNA are flanked by previously unrecognized somatic DNA enhancers and HPV L1 enhancers, with strong cis-interactions. Targeting of these enhancers by clustered regularly interspaced short palindromic repeats interference or hybrid ecDNA by bromodomain and extra-terminal inhibitor reduces E6/E7 expression, and significantly inhibites in vitro and/or in vivo growth only in ecDNA(+) models. HPV DNA in hybrid ecDNA structures are associated with previously unrecognized somatic and HPV enhancers in hybrid ecDNA that drive HPV ongogene expression and carcinogenesis, and can be targeted with ecDNA disrupting therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-57447-9

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