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

描述(申请人提供)：对表皮生长因子受体(EGFR)抑制剂的获得性耐药和肿瘤反应差是有效治疗头颈部鳞状细胞癌(HNSCC)的一个重大挑战。因此，进一步识别和表征HNSCC肿瘤对EGFR抑制反应的相关分子机制可能有助于提高药物疗效和HNSCC患者的生存。白介素6(IL-6)的产生已被证明促进HNSCC的肿瘤进展和侵袭性。然而，关于EGFR抑制剂(EGFRIs)对IL-6产生的影响，人们知之甚少。候选人观察到，与埃洛替尼敏感的HNSCC细胞相比，对EGFRI erlotinib耐药的HNSCC细胞中Toll样受体(TLR)和IL-6信号显著增加。这些观察结果导致候选人提出，慢性EGFRI治疗可能通过TLR激活诱导HNSCC肿瘤细胞产生和分泌IL-6，导致药物疗效降低、肿瘤进展和对EGFRI的获得性耐药性。此外，我们实验室的前期工作发现，EGFR途径的抑制通过激活NADPH氧化酶4(NOX4)诱导过氧化氢的产生，据报道，NOX4可以增加IL-6的表达。鉴于这些观察，EGFRIs可能刺激涉及TLRs、NOX4和IL-6的通路，导致HNSCC肿瘤细胞的炎症反应。目前的建议验证了这样的假设，即在体外和体内，通过NOX4介导的氧化应激和TLR介导的IL-6信号的激活，EGFRIs的抗肿瘤作用在HNSCC中被降低。目的1研究NOX4介导的氧化应激在EGFRIs在体外HNSCC作用机制中的作用；Aim 2将确定TLR信号在EGFRIs在体内外HNSCC作用机制中的作用；Aim 3将确定阻断IL-6通路是否能增强EGFRIs在体外和体内对HNSCC肿瘤细胞的作用。候选人期望，这项申请的成功完成将突出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将IL-6途径抑制剂与EGFRIs结合用于治疗HNSCC的新的生化原理做出贡献。

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.