HPV-Associated Head And Neck Cancer: Etiology And Determinants Of Radiation Sensitivity

HPV-associated head and neck squamous cell carcinoma (HNSCC) has overall better survival as compared to HPV-negative HNSCC. Intense multimodality therapy leads to treatment associated morbidity in patients, thereby generating a need for de-intensification strategies. Using multiple approaches and several patient cohorts, we identified a subtype of HPV+ HNSCC patients with different mutational profiles, mutational signatures, HPV gene expression patterns, HPV integration status, and patient survival. Gene set enrichment analysis of differentially expressed genes between subtypes revealed enrichment in the NF-κB pathway genes and was strongly associated with NF-κB signaling. Since radiation is the mainstay of therapy and patients whose tumors had high NF-κB activity had improved survival, we hypothesized that NF-κB -driven intrinsic tumor characteristics contribute to increased sensitivity of NF-κB active HPV+ head and neck tumors to radiation. Our studies also identified a strong inverse relationship between NF-κB activity and NRF2 signaling providing a possible mechanistic explanation of how elevated NF-κB activity sensitize cancer cells to radiation. NRF2 activity driven by mutations in KEAP or NRF2 itself is associated with radiation resistance in many cancers, including HPV-negative HNSCC; however, HPV-positive HNSCCs rarely harbor NRF2 activating mutations. Tumor subclassification based on high or low NF-κB and NRF2 signaling may help guide selection of therapeutic intensity for patients with HPV+ HNSCC.As opposed to HPV+ HNSCC with activated NF-κB and good prognosis, the subtype of tumors that do not harbor activating NF-κB mutations, can be considered as a treatment resistant high-risk group where new therapies are needed. Given that NF-κB active tumors respond better to radiation we explored whether pharmacological activation of NF-κB may improve response to therapy and decrease tumor recurrence. To accurately assess the mechanism and effectiveness of these approaches, we have developed a novel HPV mouse model with full length HPV16 in the Rosa26 locus of the mouse genome. Identification and risk stratification of subtypes of HPV+ HNSCC will serve as the foundation for new or de-intensified therapies. Tumor subclassification based on high or low NF-κB and NRF2 signaling may help guide selection of therapeutic intensity for patients with HPV+ HNSCC.