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

描述（由申请方提供）：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，进一步鉴定和表征与HNSCC肿瘤对EGFR抑制的反应相关的分子机制可能导致药物疗效和HNSCC患者生存期的改善。白细胞介素-6（IL-6）的产生已显示促进HNSCC中的肿瘤进展和侵袭性。然而，关于EGFR抑制剂（EGFRI）对IL-6产生的影响知之甚少。与厄洛替尼敏感的HNSCC细胞相比，候选人观察到对EGFRI厄洛替尼耐药的HNSCC细胞中toll样受体（TLR）和IL-6信号传导显著增加。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，肿瘤进展和对EGFRI的获得性耐药性。此外，我们实验室先前的工作已经发现，EGFR途径抑制通过激活NADPH氧化酶4（NOX 4）诱导过氧化氢产生，据报道，这会增加IL-6的表达。鉴于这些观察结果，EGFRI可能刺激涉及TLR、NOX 4和IL-6的途径，导致HNSCC肿瘤细胞中的炎症反应。目前的建议测试的假设，EGFRI的抗肿瘤作用降低HNSCC通过NOX 4介导的氧化应激和TLR介导的激活IL-6信号在体外和体内。目的1将检查NOX 4介导的氧化应激在EGFRI体外作用机制中的作用;目的2将确定TLR信号传导在EGFRI体外和体内作用机制中的作用;目的3将确定IL-6通路阻断是否会增强EGFRI体外和体内在HNSCC肿瘤细胞中的功效。候选人预计，该申请的成功完成将突出TLR、NOX 4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IL-6通路抑制剂联合EGFR治疗HNSCC提供新的生化原理。

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.