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

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.

Oncologic outcomes of salvage surgery and immune checkpoint inhibitor therapy in recurrent head and neck squamous cell carcinoma: A single‐institution retrospective study

“…p16-positivity was also not a prognostic factor at this last stage which is in line with other studies, and suggests that recurrent advanced-stage p16+ tumors may have a similar tumor phenotype to that of p16-negative disease. 17 Furthermore, a recent study by Vyas et al noted that recurrent HPV-related HNSCCs are enriched in NRF2 and OXPHOS signaling dysregulation, 18 and OXPHOS has been shown to promote platinum-based chemoresistance in ovarian cancer models. 19 p16-positive oropharyngeal disease has long been associated with improved survival over p16-negatve oropharyngeal cancer.…”

Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma

“…Notably, complex I is emerging as a therapeutic target to treat malignancies (31). For example, the complex I inhibitor IACS-010759, which we show also synergized with olaparib, has antineoplastic activity in preclinical models and was well tolerated with preliminary evidence of antitumor activity in patients (44)(45)(46)(47)(48).…”

“…4D), indicating that the drug combination created additional ROSinduced DNA damage compared to either agent alone. Second, we found that IACS-010759, an inhibitor of complex I of the mitochondrial electron transport chain that increases ROS levels and has shown preclinical activity (44)(45)(46)(47)(48), also synergized with olaparib (Supplementary Fig. S6D).…”

Nuclear factor erythroid 2‐related factor 2 in human papillomavirus‐related cancers

“…Thus, the overactivation of Nrf2 in HPV‐related cancers will affect mitochondrial cell metabolism. Indeed, it showed that Nrf2 functions as a driver of growth in oxidative phosphorylation (OXPHOS)‐dependent manner in HPV positive HNSCC 94 . This was demonstrated because the OXPHOS pathway is enriched in recurrent HPV positive HNSCC, and this enrichment in OXPHOS depends on Nrf2 expression.…”

“…This was demonstrated because the OXPHOS pathway is enriched in recurrent HPV positive HNSCC, and this enrichment in OXPHOS depends on Nrf2 expression. Thus, when Nrf2 was inhibited, OXPHOS was reduced in a parallel form 94 . Since Nrf2 protects against ROS augment and OS presence, cisplatin therapy associated with HPV positive HNSCC is refractory, pointing out the screening of patients with high levels of Nrf2 in primary and recurrent HPV positive HNSCC cells.…”