Project Summary Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide. The majority of HNSCC overexpress epidermal growth factor receptor (EGFR), an essential receptor tyrosine kinase (RTK) that promotes HNSCC growth and metastasis. Therefore, EGFR has been used as an important therapeutic target for HNSCC. However, clinical data has evidenced that only a small percentage of HNSCC patients have major responses to current anti-EGFR drugs. To improve the efficiency of anti-EGFR therapy to treat HNSCC, biomarkers that can predict sensitivity or resistance to EGFR inhibition must be identified. The candidate has observed that type I gamma phosphatidylinositol phosphate kinase i5 (PIPKI?i5) is a critical regulator of EGFR. PIPKI?i5 inhibits EGFR signaling by promoting the expression of Mitogen-Inducible Gene 6 (Mig6), an EGFR suppressor. Based on these observations, the current proposal will test the hypothesis that PIPKI?i5 regulates HNSCC sensitivity or resistance to anti-EGFR therapy by controlling EGFR signaling and trafficking. Aim 1 will determine the effect of regulating PIPKI?i5 and Mig6 expression on HNSCC response to anti-EGFR therapy using both in vitro cell line models and in vivo mouse models. The levels of PIPKI?i5 and Mig6 in HNSCC patients' cancer tissues will also be evaluated. Aim 2 will explore the mechanisms by which PIPKI?i5 controls cell signaling events associating with HNSCC response to anti-EGFR therapy. The candidate expects that the successful completion of this application will reveal a novel PIPKI?i5-regulated pathway that controls HNSCC sensitivity and/or resistance to anti-EGFR therapy.