Mechanisms Determining Dysregulation of the NRF2 Oxidative Stress Response in Head and Neck Squamous Cell Carcinoma

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ABSTRACT The principle investigator, Dr. Travis Schrank, MD, PhD, is a first-year faculty member in the University of North Carolina Department of Otolaryngology. He has been hired in a surgeon-scientist role and presently has 75% protected time for research. His past training in computational biophysics and experimental biochemistry have motivated and equipped him pursue an independent research career in computational genomics and head and neck cancer molecular biology. The presented research aims are an outgrowth of the PI's ongoing efforts to improve RNA based methods for identifying NRF2 active head and neck squamous cell carcinoma (HNSCC) tumors. NRF2 is the key transcriptional regulator of the cellular oxidative stress response, and has been related to poor patient outcome and radiation response in multiple cancer types. Mutational activation of NRF2 is observed in 8% of HPV negative (HPV-) HNSCC. However, our estimates based on RNA transcription suggest that NRF2 is aberrantly activated in 24% of HPV- HNSCC. This work has identified atypical NRF2 and CUL3 variants which are associated with NRF2 activation. The functional consequences of these variants will be investigated (Aim 1). We also find that the prohormone Neurotensin is highly expressed in NRF2 active HNSCC tumors without NRF2 pathway mutations. Our preliminary data suggest that pro-Neurotensin may activate NRF2, through a previously unreported interaction with KEAP1 (a regulator of NRF2 stability). This novel function of pro-Neurotensin will be investigated in Aim 2. Suppression of NRF2 activity is well known to radio-sensitize cancer cells. We have also identified a partially suppressed pattern of NRF2 target expression in HPV associated (HPV+) HNSCC tumors, which are highly sensitive to radiation. p14ARF is also highly expressed in HPV+ HNSCC, binds NRF2, and suppresses transactivation of some NRF2 targets. Aim 3 will explore the hypothesis that NRF2 target suppression due to high levels of p14ARF, contributes to the radio-sensitivity of these tumors. The proposed work will be impactful for several reasons, 1) the tumor subclassification method developed address the very common problem of imperfect clinical/genomic annotations of tumor RNA expression data, 2) the first known/reported signaling role for the prohormone form of Neurotensin will be explored, and 3) identification of NRF2 targets associated with radiation response may suggest novel approaches to treatment. UNC has exceptionally strong institutional expertise and resources related to cancer genomics. The mentorship committee also has key project specific expertise in NRF2 biology, computational genomics, p14ARF and Neurotensin. Collectively the mentorship team has previously trained four K award recipients and includes two surgeon-scientists who can provide critical career guidance.