Role of inflammation in resistance to EGFR inhibitors in head and neck cancer

炎症在头颈癌 EGFR 抑制剂耐药性中的作用

• 批准号: 9270538
• 负责人: Andrean Llewela Burnett
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-02 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270538
• 关键词: Adaptor Signaling Protein; Biochemical; Cell Line; Chronic; Clinical; Data; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Gene Expression; Genes; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Hydrogen Peroxide; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin Activation; Interleukin-6; Kinetics; Laboratories; Lead; Malignant Epithelial Cell; Measures; Mediating; Molecular; Morbidity - disease rate; MyD88 protein; NADPH Oxidase; Neoplasm Metastasis; Oxidative Stress; Pathway Analysis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Play; Predisposition; Production; Publishing; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recurrence; Reporting; Resistance; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Survival Rate; Testing; Toll-like receptors; Transcription Factor AP-1; Tumor Promotion; Work; Xenograft procedure; angiogenesis; antitumor effect; base; cell killing; chemotherapy; cytotoxicity; drug efficacy; effective therapy; genetic manipulation; improved; improved outcome; in vivo; inhibitor/antagonist; knock-down; migration; mouse model; neoplastic cell; overexpression; public health relevance; receptor expression; response; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): Acquired resistance and poor tumor response to epidermal growth factor receptor (EGFR) inhibitors is a significant challenge for effective treatment of head and neck squamous cell carcinoma (HNSCC). Therefore, further identification and characterization of molecular mechanisms associated with HNSCC tumor response to EGFR inhibition could lead to improvements in drug efficacy and HNSCC patient survival. Interleukin-6 (IL-6) production has been shown to promote tumor progression and invasiveness in HNSCC. However little is known about the effect of EGFR inhibitors (EGFRIs) on IL-6 production. The candidate has observed a profound increase in toll-like receptor (TLR) and IL-6 signaling in HNSCC cells resistant to the EGFRI erlotinib compared to erlotinib-sensitive HNSCC cells. These observations led the candidate to the proposal that chronic EGFRI treatment may induce the production and secretion of IL-6 in HNSCC tumor cells via TLR activation, leading to reduced drug efficacy, tumor progression and acquired resistance to EGFRIs. Additionally, prior work in our laboratory has found that EGFR pathway inhibition induced hydrogen peroxide production via activation of NADPH oxidase 4 (NOX4), which has been reported to increase IL-6 expression. Given these observations, EGFRIs may stimulate pathways involving TLRs, NOX4 and IL-6, leading to an inflammatory response in HNSCC tumor cells. The current proposal tests the hypothesis that the antitumor effects of EGFRIs are reduced in HNSCC via NOX4-mediated oxidative stress and TLR-mediated activation of IL-6 signaling in vitro and in vivo. Aim 1 will examine the role of NOX4-mediated oxidative stress in the mechanism of action of EGFRIs in HNSCC in vitro; Aim 2 will determine the contribution of TLR signaling in the mechanism of action of EGFRIs in HNSCC in vitro and in vivo; and Aim 3 will determine if IL-6 pathway blockade would enhance the efficacy of EGFRIs in HNSCC tumor cells in vitro and in vivo. The candidate expects that the successful completion of this application will highlight the significance of TLR, NOX4 and IL-6-mediated inflammation in EGFR-based chemotherapy and contribute in a meaningful way to a new biochemical rationale for the use of IL-6 pathway inhibitors in combination with EGFRIs for the treatment of HNSCC.

描述（由申请人提供）：对表皮生长因子受体（EGFR）抑制剂的获得性耐药性和较差的肿瘤反应是有效治疗头颈鳞状细胞癌（HNSCC）的重大挑战。因此，进一步鉴定和表征与 HNSCC 肿瘤对 EGFR 抑制反应相关的分子机制可能会提高药物疗效和 HNSCC 患者生存率。白细胞介素 6 (IL-6) 的产生已被证明可促进 HNSCC 的肿瘤进展和侵袭性。然而，人们对 EGFR 抑制剂 (EGFRIs) 对 IL-6 产生的影响知之甚少。该候选者观察到，与对厄洛替尼敏感的 HNSCC 细胞相比，对 EGFRI 厄洛替尼耐药的 HNSCC 细胞中 Toll 样受体 (TLR) 和 IL-6 信号显着增加。这些观察结果使候选人提出，长期 EGFRI 治疗可能通过 TLR 激活诱导 HNSCC 肿瘤细胞产生和分泌 IL-6，从而导致药效降低、肿瘤进展和对 EGFRIs 的获得性耐药。此外，我们实验室之前的工作发现，EGFR 通路抑制通过激活 NADPH 氧化酶 4 (NOX4) 诱导过氧化氢产生，据报道，NADPH 氧化酶 4 (NOX4) 会增加 IL-6 的表达。鉴于这些观察结果，EGFRIs 可能会刺激涉及 TLR、NOX4 和 IL-6 的通路，从而导致 HNSCC 肿瘤细胞发生炎症反应。目前的提案测试了这样的假设：EGFRIs 在 HNSCC 中的抗肿瘤作用通过 NOX4 介导的氧化应激和 TLR 介导的体外和体内 IL-6 信号传导激活而降低。目标 1 将在体外研究 HNSCC 中 EGFRIs 作用机制中 NOX4 介导的氧化应激的作用；目标 2 将确定 TLR 信号传导在 HNSCC 体外和体内 EGFRIs 作用机制中的贡献；目标 3 将确定 IL-6 途径阻断是否会增强 EGFRIs 在体外和体内 HNSCC 肿瘤细胞中的功效。候选人预计该申请的成功完成将凸显 TLR、NOX4 和 IL-6 介导的炎症在基于 EGFR 的化疗中的重要性，并以有意义的方式为使用 IL-6 途径抑制剂的新生化原理做出贡献与 EGFRIs 联合治疗 HNSCC。