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

Mig6 表达和 HNSCC 对抗 EGFR 治疗反应的新型磷酸肌醇调节途径

• 批准号: 9244954
• 负责人: Yue Sun
• 金额: $ 11.44万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244954
• 关键词: 4-Nitroquinoline-1-oxide; Biological Markers; Cancer Patient; Cell Differentiation process; Cell Line; Cell Proliferation; Cetuximab; Chemicals; Clinical Data; Data; Down-Regulation; Drug Receptors; Drug Targeting; Epidermal Growth Factor Receptor; Event; Genes; Growth; Head and Neck Squamous Cell Carcinoma; In Vitro; Knockout Mice; Laboratories; Learning; Legal patent; Link; Lung Adenocarcinoma; Lysosomes; Malignant Neoplasms; Mitogens; Modeling; Monoclonal Antibodies; Mus; Mutation; Neoplasm Metastasis; Nuclear Translocation; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphotransferases; Receptor Activation; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recurrence; Research; Resistance; Role; Sampling; Signal Transduction; Sorting - Cell Movement; Testing; Therapeutic; Tissues; Tumor Suppressor Proteins; Ubiquitination; base; cancer therapy; effective therapy; improved; in vivo; knock-down; mouse model; novel; novel strategies; outcome forecast; overexpression; predicting response; public health relevance; receptor-mediated signaling; response; small molecule inhibitor; therapeutic target; trafficking; tumor; tumor progression

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.

项目摘要 头颈部鳞状细胞癌(HNSCC)是全球第六大最常见的癌症。大多数人 HNSCC过表达必需受体酪氨酸激酶(RTK)的表皮生长因子受体(EGFR) 这会促进HNSCC的生长和转移。因此，EGFR已被用作一种重要的治疗手段。 HNSCC的目标。然而，临床数据表明，只有一小部分HNSCC患者有 对当前抗EGFR药物的主要反应。为了提高抗EGFR治疗HNSCC的效率， 必须确定能够预测对EGFR抑制的敏感性或耐药性的生物标志物。候选人有 发现I型磷脂酰肌醇磷酸激酶I5(PIPKIγI5)是表皮生长因子受体的关键调节因子。 PIPKIγi5通过促进有丝分裂原诱导基因6(MIG6)的表达抑制EGFR信号转导 抑制者。基于这些观察，目前的提议将检验PIPKIγi5调节的假设 通过控制EGFR信号和转运，HNSCC对抗EGFR治疗的敏感性或耐药性。目标1将 确定调节PIPKI、γi5和Mig6的表达对HNSCC抗EGFR治疗反应的影响 使用体外细胞系模型和体内小鼠模型。HNSCC组织中PIPKI、γI5和MIG6的表达 患者的癌症组织也将得到评估。Aim 2将探索PIPKIγi5控制的机制 细胞信号事件与HNSCC对抗EGFR治疗的反应相关。候选人预计， 这项申请的成功完成将揭示一个新的PIPKIγi5调节的途径，它控制着HNSCC 对抗EGFR治疗的敏感性和/或耐药性。