Interactions between inflammatory and oncogenic signaling pathways in GBM

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。EGFR野生型是最常见的EGFR类型 在人类癌症中表达。然而，表达EGFRwt的肿瘤并不是癌基因成瘾和EGFR 抑制作为一种治疗方法通常是无效的。在这里，我们提出了一种调解初级 胶质母细胞瘤(GBM)细胞对厄洛替尼的耐药性及其克服策略。EGFR基因扩增和 突变在基底膜中很常见，但抑制EGFR对治疗这种肿瘤并不有效。我们建议 过度表达GBMS的EGFR的主要耐药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， 包括RTK Axl的激活和ERK的下游激活。我们建议JNK扮演主人公 Erlotinib的调节器触发的生存信号。因此，厄洛替尼暴露会导致肿瘤坏死因子分泌增加， 导致JNK的激活。JNK的激活通过增加Gas6的分泌而导致Axl的激活 AXL的配体和AXL诱导ERK激活。因此，我们认为，对EGFR抑制的主要抗性在 胶质瘤细胞是肿瘤坏死因子-JNK-Axl-ERK通路激活的结果。在具体目标1中：我们阐明 厄洛替尼诱导JNK活化的机制。厄洛替尼诱导的JNK激活很重要，因为JNK 作为对EGFR抑制的反应，触发关键的生存信号。我们假设肿瘤坏死因子在 厄洛替尼可诱导JNK活化。在特定目标2中，我们研究了调节原发抗性的机制。 Erlotinib在胶质瘤细胞中的作用，并验证JNK激活导致受体激活的假设 酪氨酸激酶Axl和ERK的下游激活，以及这个JNK-Axl-ERK轴介导原发 对厄洛替尼的耐药性。在特定的目标3中，我们检测了联合抑制EGFR和 检测适应性生存中断假说的临床前小鼠模型中的肿瘤坏死因子或JNK或Axl 由EGFR抑制触发的信号将把具有原发耐药的癌症转变为可以 经EGFR抑制有效治疗。由于EGFR和肿瘤坏死因子抑制剂都在临床上使用，这种方法 可以在患者身上快速测试。

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. EGFR wild type (EGFRwt) is the most common EGFR type expressed in human cancer. However, tumors expressing EGFRwt are not oncogene addicted and EGFR inhibition is generally ineffective as a treatment. Here, we propose a mechanism that mediates primary resistance to Erlotinib in glioblastoma (GBM) cells and a strategy to overcome it. EGFR gene amplification and mutation are common in GBM, but EGFR inhibition has not been effective in treating this tumor. We propose that the primary resistance of EGFR overexpressing 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 RTK Axl and downstream activation of ERK. We propose that JNK acts as a master regulator of Erlotinib-triggered survival signals. Thus, Erlotinib exposure leads to increased TNF secretion, leading to activation of JNK. JNK activation leads to activation of Axl via increased secretion of GAS6, the ligand for Axl, and Axl induced ERK activation. Thus, we propose that primary resistance to EGFR inhibition in glioma cells results from activation of a TNF-JNK-Axl-ERK pathway. In Specific Aim 1: We elucidate the mechanism of Erlotinib-induced JNK activation. Erlotinib induced JNK activation is important because JNK triggers key survival signals as a response to EGFR inhibition. WE hypothesize that TNF plays a key role in Erlotinib induced JNK activation. In Specific Aim 2 we examine the mechanisms mediating primary resistance to Erlotinib in glioma cells and examine the hypothesis that JNK activation results in activation the receptor tyrosine kinase Axl and downstream activation of ERK, and that this JNK-Axl-ERK axis mediates primary resistance to Erlotinib. In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and TNF or JNK or Axl in a preclinical mouse model examining the hypothesis that interruption of adaptive survival signaling triggered by EGFR inhibition will transform cancers with primary resistance into cancers that can be effectively treated by EGFR inhibition. Since both EGFR and TNF inhibitors are in clinical use, this approach could be rapidly tested in patients.