Inflammation and EGFR crosstalk in HNSCC Therapy

Project Summary Given the importance of oncogenic epidermal growth factor receptor (EGFR) signaling for tumor cell proliferation in head and neck squamous cell carcinoma (HNSCC), we believe that EGFR inhibition remains worthy as a strategy to be included in radiotherapy (RT) protocols for HNSCC and that further investigation of

mechanisms responsible for poor response to EGFRIs is warranted. Based on our preliminary data, we propose that increased interleukin-1 (IL-1) signaling may lead to sustained interleukin-8 (IL-8) signaling and NADPH oxidase 2 (NOX2)-derived superoxide (O2.-) production which is associated with pro-survival signaling and an

immunosuppressive tumor microenvironment leading to poor response to EGFRIs. As a result, targeting the IL-1 signaling pathway may enhance HNSCC tumor response to EGFRIs combined with RT. The overall hypothesis of this grant application is that NOX2 redox activity and IL-8 signaling contribute to poor long-term

anti-tumor response to EGFRIs via increased IL-1 signaling in RT-treated HNSCC tumors. Aim 1 will determine if IL-1-mediated NOX2 redox activity is involved in poor HNSCC tumor response to RT+EGFRIs; Aim 2 will determine if IL-1-mediated IL-8 signaling is involved in poor HNSCC tumor response to RT+EGFRIs; and Aim 3 will determine if inhibition of IL-1 signaling would enhance HNSCC tumor response to

RT+EGFRIs. Overall, we expect that this application will highlight novel redox mechanisms associated with poor response to EGFRIs and possibly lead to promising new therapeutic approaches for RT-treated HNSCC patients.