Abstract 6164: NF-κB and NRF2 signaling pathways affect prognosis in HPV-associated head and neck cancer

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Abstract Incidence of HPV associated head and neck squamous cell carcinoma (HNSCC) is on the rise, displaying a significantly favorable prognosis and overall better survival as compared to HPV negative HNSCC. Intense radiotherapy is the primary medical care leading to treatment associated morbidity in patients, thereby generating a need for de-intensification strategies. Biomarkers that can identify patients with less aggressive tumors as candidates for de-escalation therapy would revolutionize treatment. We applied an unbiased approach (weighted gene correlation network analysis (WGCNA)) that allows detection of autocorrelated gene sets on 3 independent cohorts of HPV+ HNSCC and created 22 consensus transcriptional modules by selecting genes that grouped together in WGCNA analyses from all 3 cohorts. Interestingly, only 1 module intrinsically divided HPV+ HNSCC into 2 subtypes, displaying different mutational profiles, mutational signatures, HPV gene expression patterns, HPV integration status, and patient survival. Gene set enrichment analysis revealed that this module was enriched in NF-kB genes and strongly associated with NF-κB signaling, confirming our prior findings that defined HPV+ HNSCC subtypes by presence or absence of NF-kB regulators, TRAF3 or CYLD defects and by the NF-κB activity classifier. Our studies show that NF- κB -driven intrinsic tumor characteristics contribute to increased sensitivity of NF- κB active HPV+ head and neck tumors to radiation, providing patients survival benefits. Indeed, TRAF3 or CYLD deletion activated NF-kB and dramatically increased radiation sensitivity of HPV+ head and neck cancer cells. In line with our RNA seq analysis, we found that activation of NF-κB via TRAF3/CYLD deletion significantly correlated with marked downregulation of NRF2 activity and reduced nuclear localization in in HPV+ HNSCC cells. Interestingly, TRAF3 CRISPR KO cells had lower NRF2 protein levels that were restored by MG132 treatment, indicating an involvement of KEAP1/CUL3 mediated proteasomal degradation of NRF2. In summary, our data unveils a unique relation between NF-κB pathway and radiosensitivity in HPV+ HNSCC. The distinct biological characteristics that separate patients into two subclasses associated with favorable prognosis could serve as a biomarker for personalized therapy. Citation Format: Aditi Kothari, Travis Parke Schrank, Wendell Gray Yarbrough, Natalia Isaeva. NF-κB and NRF2 signaling pathways affect prognosis in HPV-associated head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6164.