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Elucidation of Nrf2 Signalling in the Molecular Pathogenesis of Human Papillomavirus Associated Head and Neck Squamous Cell Carcinoma (Paperback)
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In the last 15 years, research has provided enough evidence to identify Human Papillomavirus associated Head & neck squamous cell carcinomas (HPV+ve HNSCC) as a distinct clinical entity with unique risk factors, pathogenesis and clinico-pathological characteristics. The distinctive feature making it different from HPV-ve HNSCC is that they show better treatment response, higher survival rates and lower risks of recurrence rate. Many retrospective and prospective studies have shown that independent of the treatment modality; HPV+ve patients have overall survival of 80% whereas HPV-ve patients are at about 50%. Despite recognizing favourable prognosis in HPV+ve HNSCC patients, the underlying molecular mechanisms on how HPV infection enhances sensitivity to anticancer drugs remains poorly understood. Due to lack of mechanistic understandings, other than HPV status, there are no predictive prognostic biomarkers to identify good responders to chemoradiotherapy among HPV+ve HNSCC patients. Hence, these patients are subjected to similar intensive chemoradiotherapy regimen as HPV-ve HNSCC causing immense morbidity and mortality. De-escalation of chemo-radiation dose is being actively contended for treatment of HPV-driven HNSCC but has not been successful. In short, there is an unmet need to develop sensitive, specific, and reliable biomarkers to identify good responders and for guiding treatment modality of HPV+ve HNSCC patients. Transcription factor NRF2 (Nuclear factor E2-related factor 2) is a master regulator of cell survival pathways. In wide range of cancers (lung, breast, colon), there is an aberrant constitutive activation of NRF2 resulting in basally higher expression of antioxidant defenses and phase II drug detoxification enzymes, which confers proliferative advantage and resistance to chemo radiation therapy to cancer cells. The low incidence of somatic mutations in NRF2 pathway suggest that HPV+ve HNSCC patients are likely to be associated with low NRF2 activity as compared to HPV-ve HNSCC patients. A growing body of evidence suggests that viral infection in epithelial and immune cells may cause activation or repression of NRF2 signaling. Thus, we asked whether high-risk HPV infection represses NRF2 signaling in cancer cells and whether that has any implications in the observed sensitivity to chemoradiotherapy in HPV associated Head & Neck cancers.