A Novel Phosphoinositide-regulated Pathway in Mig6 Expression and HNSCC Response to Anti-EGFR Therapy

项目摘要 头颈部鳞状细胞癌（HNSCC）是全球第六大流行癌症。大多数 表皮生长因子受体（EGFR），一种必需的受体酪氨酸激酶（RTK） 促进HNSCC生长和转移。因此，EGFR已被用作重要的治疗药物， HNSCC的目标。然而，临床数据已经证明，只有一小部分HNSCC患者 目前抗EGFR药物的主要反应。为了提高抗EGFR疗法治疗HNSCC的效率， 必须鉴定可预测对EGFR抑制的敏感性或抗性的生物标志物。这位候选人有 观察到I型γ磷脂酰肌醇磷酸激酶i5（PIPKIγi5）是EGFR的关键调节剂。 PIPKIγ 15通过促进促分裂原诱导基因6（Mig 6）的表达来抑制EGFR信号传导， 抑制器。基于这些观察结果，目前的提议将检验PIPKIγi5调节 HNSCC通过控制EGFR信号传导和运输对抗EGFR治疗敏感或耐药。目标1将 确定调节PIPKIγ 15和Mig 6表达对HNSCC对抗EGFR治疗的应答的影响 使用体外细胞系模型和体内小鼠模型。PIPKIγ 15和Mig 6在HNSCC中的表达 病人的癌组织亦会接受评估。目的2探讨PIPKIγi5调控细胞凋亡的机制 与HNSCC对抗EGFR治疗的反应相关的细胞信号传导事件。候选人预计， 本申请的成功完成将揭示控制HNSCC的新的PIPKIγ 15调节途径 敏感性和/或对抗EGFR治疗的抗性。

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 (PIPKIγi5) is a critical regulator of EGFR. PIPKIγi5 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 PIPKIγi5 regulates HNSCC sensitivity or resistance to anti-EGFR therapy by controlling EGFR signaling and trafficking. Aim 1 will determine the effect of regulating PIPKIγi5 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 PIPKIγi5 and Mig6 in HNSCC patients' cancer tissues will also be evaluated. Aim 2 will explore the mechanisms by which PIPKIγi5 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 PIPKIγi5-regulated pathway that controls HNSCC sensitivity and/or resistance to anti-EGFR therapy.