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

抑制表皮生长因子受体（EGFR）信号传导是靶向治疗肿瘤的重要途径。 癌症的治疗。然而，尽管异常的EGFR信号传导在癌症中广泛存在，但EGFR抑制在癌症中仍然存在。 主要仅在表达特定EGFR突变的有限数量的肺癌中有效， 致癌基因成瘾因此，使具有原发性EGFR抗性的癌细胞对EGFR敏感的能力， 考虑到EGFR过度表达癌症的广泛流行，抑制可能具有巨大的临床价值 对EGFR抑制具有原发性抗性。异常表皮生长因子受体（EGFR）信号传导是 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。没有靶向治疗对GBM有效。EGFR基因扩增和突变是 在GBM中是常见的，并且已经进行了GBM中EGFR抑制的多项试验。然而，EGFR 抑制在GBM中尚未成功。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性的机制。在这里，我们提出一个 介导GBM中对EGFR抑制的原发性耐药性的机制以及克服它的策略。我们 提出表达EGFR的GBM的原发性耐药性是由快速适应性反应引起的， 防止EGFR信号的突然丢失导致细胞死亡。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的神经胶质瘤细胞，厄洛替尼触发快速稳态应答， 涉及转录因子Nrf2信号网络的激活。NRF2调节关键下游信号传导 这些网络是GBM中对EGFR抑制的治疗抗性的关键介质。我们的初步数据 表明EGFR和Nrf2的联合抑制克服了GBM对EGFR的原发性抗性 在细胞培养物中以及在GBM的原位模型中的抑制。在具体目标1中：我们检查效应器 神经胶质瘤细胞中Nrf2的下游机制介导对EGFR抑制的原发性抗性 在具体目标2中，我们研究了调节EGFR抑制后Nrf2激活的机制。 在GBM。在具体目标3中，我们检查了EGFR和Nrf2或Nrf3的联合抑制的生物学效应。 在临床前小鼠原位模型中抑制Nrf2下游的关键信号传导网络， 由EGFR抑制触发的适应性存活信号传导的中断将转化GBM的假设 对可通过EGFR抑制有效治疗的癌症具有原发性抗性。由于EGFR和 Nrf2抑制剂已在临床上使用，这种方法可以在患者中快速测试。该提案涉及 GBM管理中未满足的关键需求，并可能对GBM的方式产生变革性影响。 治疗。

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.