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

描述（由申请人提供）：获得性耐药和对表皮生长因子受体（EGFR）抑制剂的不良肿瘤反应是头颈部鳞状细胞癌（HNSCC）有效治疗的重大挑战。因此，进一步鉴定和表征HNSCC肿瘤对EGFR抑制反应的相关分子机制可能会提高药物疗效和HNSCC患者的生存率。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。该候选人观察到，与厄洛替尼敏感的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信号的显著增加。这些观察结果使候选人提出慢性EGFRI治疗可能通过TLR激活诱导HNSCC肿瘤细胞中IL-6的产生和分泌，导致药物疗效降低，肿瘤进展和获得性对EGFRI的耐药。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）诱导过氧化氢的产生，据报道，过氧化氢会增加IL-6的表达。鉴于这些观察结果，EGFRIs可能刺激涉及tlr、NOX4和IL-6的通路，导致HNSCC肿瘤细胞的炎症反应。目前的提案在体外和体内验证了EGFRIs在HNSCC中通过nox4介导的氧化应激和tlr介导的IL-6信号激活而降低抗肿瘤作用的假设。目的1将研究nox4介导的氧化应激在体外HNSCC中EGFRIs作用机制中的作用；目的2将确定TLR信号在体外和体内EGFRIs在HNSCC中的作用机制中的贡献；Aim 3将确定IL-6通路阻断是否会增强EGFRIs在体外和体内对HNSCC肿瘤细胞的作用。候选人希望此次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使用IL-6途径抑制剂与EGFRIs联合治疗HNSCC提供新的生化依据。

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.