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Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation

Avani Vyas, View ORCID ProfileR. Alex Harbison, Daniel Faden, Mark Kubik, Drake Palmer, Qing Zhang, Hatice U. Osmanbeyoglu, Eduardo Méndez, Umamaheswar Duvvuri
doi: https://doi.org/10.1101/2020.08.21.261206
Avani Vyas
1Departments of Otolaryngology, University of Pittsburgh School of Medicine
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R. Alex Harbison
2Department of Otolaryngology, University of Washington School of Medicine
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  • ORCID record for R. Alex Harbison
Daniel Faden
3Department of Otolaryngology, Massachusetts Eye and Ear Infirmary
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Mark Kubik
1Departments of Otolaryngology, University of Pittsburgh School of Medicine
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Drake Palmer
4Department of Biological Sciences, University of Pittsburgh School of Arts & Sciences
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Qing Zhang
5Genomics & Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center
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Hatice U. Osmanbeyoglu
6Biomedical Informatics, University of Pittsburgh School of Medicine
7Department of Bioengineering, University of Pittsburgh School of Engineering
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Eduardo Méndez
2Department of Otolaryngology, University of Washington School of Medicine
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Umamaheswar Duvvuri
1Departments of Otolaryngology, University of Pittsburgh School of Medicine
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  • For correspondence: duvvuriu@upmc.edu
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Abstract

Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, ~10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear. Here, we show that the oxidative phosphorylation (OXPHOS) pathway is enriched in recurrent HPV-associated HNSC and may contribute to treatment failure. Nrf2-enriched HNSC samples from the Cancer Genome Atlas with enrichment in OXPHOS, fatty acid metabolism, Myc, Mtor, ROS, and glycolytic signaling networks exhibited worse survival. HPV-positive HNSC cells demonstrated sensitivity to the OXPHOS inhibitor, IACS-010759, in a Nrf2-dependent manner. Further, using murine xenograft models, we identified Nrf2 as a driver of tumor growth. Mechanistically, Nrf2 drives ROS and mitochondrial respiration, and Nrf2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. Nrf2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSC cells. Cisplatin treatment demonstrated Nrf2-dependent synergy with OXPHOS inhibition. These results unveil a paradigm shifting translational target harnessing Nrf2-mediated metabolic reprogramming in HPV-related HNSC.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Financial Support, This study is supported by I01 BX-003456, R01 DE028343, R00 CA207871 and the Mosites Fund for personalized medicine.

  • Conflicts of Interest, The authors have no conflicts of interest to declare.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 22, 2020.
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Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation
Avani Vyas, R. Alex Harbison, Daniel Faden, Mark Kubik, Drake Palmer, Qing Zhang, Hatice U. Osmanbeyoglu, Eduardo Méndez, Umamaheswar Duvvuri
bioRxiv 2020.08.21.261206; doi: https://doi.org/10.1101/2020.08.21.261206
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Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation
Avani Vyas, R. Alex Harbison, Daniel Faden, Mark Kubik, Drake Palmer, Qing Zhang, Hatice U. Osmanbeyoglu, Eduardo Méndez, Umamaheswar Duvvuri
bioRxiv 2020.08.21.261206; doi: https://doi.org/10.1101/2020.08.21.261206

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