The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma

抑制表皮生长因子受体(EGFR)信号转导是靶向治疗的重要途径 癌症的治疗。然而，尽管异常的EGFR信号在癌症中广泛存在，但EGFR抑制 主要只对有限数量的表达特定EGFR突变的肺癌有效，并且 癌基因成瘾。因此，使具有原代EGFR耐药的癌细胞对EGFR敏感的能力 考虑到egfr过度表达癌症的广泛流行，抑制具有潜在的临床价值。 具有对EGFR抑制的原发耐药性。表皮生长因子受体(EGFR)异常信号转导 常见于胶质母细胞瘤(GBM)。GBM是一种毁灭性的疾病，即使有最好的治疗， 预后很差。对于GBM，没有靶向治疗是有效的。EGFR基因扩增和突变 在GBM中很常见，并且已经进行了多项关于抑制GBM中EGFR的试验。然而，EGFR 在GBM中，抑制作用并不成功。GBM靶向治疗的失败导致了密集的 努力了解介导靶向治疗耐药的机制。在这里，我们提出一种 GBM对EGFR抑制的原发耐药机制及其克服策略。我们 认为EGFR表达GBMS的主要抗性是快速适应反应的结果 防止细胞因突然失去EGFR信号而死亡。这种适应性反应可以在胶质瘤中检测到。 表达EGFRwt或致癌EGFRvIII突变体的细胞。我们的初步数据显示， 表达EGFRwt或EGFRvIII，Erlotinib的胶质瘤细胞触发快速稳态反应， 涉及转录因子Nrf2信号网络的激活。NRF2调节关键下行信令 这些网络是GBM对EGFR抑制的治疗抵抗的关键媒介。我们的初步数据 提示EGFR和Nrf2的联合抑制克服了GBM对EGFR的原发耐药性 在细胞培养中的抑制以及在GBM的原位模型中。具体目标1：我们检查效应器 Nrf2下游介导胶质瘤细胞对EGFR抑制的原发耐药机制 在特定的目标2中，我们研究了调节Nrf2激活以响应EGFR抑制的机制 单位为GBM。在特定的目标3中，我们检测了联合抑制EGFR和Nrf2或 在临床前小鼠原位模型中抑制Nrf2下游的关键信号网络 假设EGFR抑制触发的适应性生存信号的中断将改变基底膜 具有原发耐药性的癌症可以通过抑制EGFR有效地治疗。由于EGFR和 NRF2抑制剂正在临床使用，这种方法可以在患者身上快速测试。该提案涉及 GBM管理中未得到满足的关键需求，并可能对GBM的方式产生变革性影响 治疗过了。

Inhibition of epidermal growth factor receptor (EGFR) signaling is an important approach to the targeted treatment of cancer. However, although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is primarily effective only in a limited number of lung cancers that express specific EGFR mutations and are oncogene addicted. Thus, the ability to render cancer cells with primary EGFR resistance sensitive to EGFR inhibition is potentially of enormous clinical value, given the wide prevalence of EGFR overexpressing cancers with primary resistance to EGFR inhibition. Aberrant epidermal growth factor receptor (EGFR) signaling is common in glioblastoma (GBM). GBM is a devastating disease and, even with the best treatment, the prognosis is dismal. No targeted treatment is effective in GBM. EGFR gene amplification and mutation are common in GBM and multiple trials of EGFR inhibition in GBM have been conducted. However, EGFR inhibition has not been successful in GBM. The failure of targeted treatments in GBM has led to an intensive effort to understand mechanisms that mediate resistance to targeted treatment. Here, we propose a mechanism that mediates primary resistance to EGFR inhibition in GBM and a strategy to overcome it. We propose that the primary resistance of EGFR expressing GBMs results from a rapid adaptive response that prevents cell death from a sudden loss of EGFR signaling. This adaptive response can be detected in glioma cells expressing either EGFRwt or the oncogenic EGFRvIII mutant. Our preliminary data indicate that in glioma cells expressing either EGFRwt or EGFRvIII, Erlotinib triggers a rapid homeostatic response that involves activation of the transcription factor Nrf2 signaling network. Nrf2 regulates key downstream signaling networks that are critical mediators of therapeutic resistance to EGFR inhibition in GBM. Our preliminary data indicate that a combined inhibition of EGFR and Nrf2 overcomes the primary resistance of GBMs to EGFR inhibition in cell culture as well as in an orthotopic model of GBM. In Specific Aim 1: we examine the effector mechanisms downstream of Nrf2 that mediate mediating primary resistance to EGFR inhibition in glioma cells In Specific Aim 2 we examine the mechanisms that regulate activation of Nrf2 in response to EGFR inhibition in GBM. In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and Nrf2 or inhibition of key signaling networks downstream of Nrf2 in a preclinical mouse orthotopic model examining the hypothesis that interruption of adaptive survival signaling triggered by EGFR inhibition will transform GBMs with primary resistance into cancers that can be effectively treated by EGFR inhibition. Since both EGFR and Nrf2 inhibitors are in clinical use, this approach could be rapidly tested in patients. The proposal addresses critical unmet needs in the management of GBM, and could have a transformative impact on the way GBM is treated.