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

Purpose: Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSCC). 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. Experimental Design: We performed RNA seq on tissues from matched primary (pOPSCC) and metachronous recurrent cancers (rOPSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (1) NRF2 overexpression on growth in vitro and in vivo (2) OXPHOS inhibition using IACS-010759 on NRF2 dependent cells (3) combination of cisplatin and OXPHOS inhibition. Results: The oxidative phosphorylation (OXPHOS) pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC 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 HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, 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 HNSCC cells. Conclusions: These results unveil a paradigm shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.