Interactions between inflammatory and oncogenic signaling pathways in GBM

GBM 炎症和致癌信号通路之间的相互作用

• 批准号: 10266003
• 负责人: AMYN HABIB
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266003
• 关键词: Automobile Driving; Biological; Cell Death; Cells; Clinical; Data; Disease; Drug resistance; EGFR Gene Amplification; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exhibits; Failure; Feedback; Gene Mutation; Glioblastoma; Glioma; Growth; Homeostasis; Human; Inflammatory; Interruption; Lead; Lesion; Ligands; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Mutation; Nature; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prevalence; Protein Tyrosine Kinase; Receptor Activation; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; TNF gene; Testing; Thalidomide; Tyrosine Kinase Inhibitor; axl receptor tyrosine kinase; cancer cell; cancer therapy; clinically relevant; combinatorial; cytokine; epidermal growth factor receptor VIII; improved; inhibitor/antagonist; mouse model; mutant; overexpression; pre-clinical; prevent; resistance mechanism; response; targeted treatment; tumor; tumor growth; vaccine trial

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.

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。EGFR野生型（EGFRwt）是最常见的EGFR类型 在人类癌症中表达。然而，表达EGFRwt的肿瘤不是癌基因成瘾的，EGFR 抑制作为治疗通常是无效的。在这里，我们提出了一种机制，调解主要 在胶质母细胞瘤（GBM）细胞中对厄洛替尼的抗性和克服它的策略。 突变在GBM中是常见的，但EGFR抑制在治疗这种肿瘤中并不有效。我们提出 EGFR过表达GBM的原发性耐药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RTK Axl的激活和ERK的下游激活。我们建议JNK充当主人 Erlotinib触发的生存信号的调节剂。因此，厄洛替尼暴露导致TNF分泌增加， 导致JNK的激活。JNK激活通过增加GAS 6的分泌导致Axl的激活， Axl的配体，并且Axl诱导ERK活化。因此，我们认为，原发性耐药EGFR抑制， 神经胶质瘤细胞是由TNF-JNK-Axl-ERK途径的激活引起的。具体目标1：我们阐明 厄洛替尼诱导的JNK激活机制。厄洛替尼诱导的JNK活化是重要的，因为JNK 触发关键的生存信号作为对EGFR抑制的响应。我们假设TNF在 厄洛替尼诱导JNK活化。在具体目标2中，我们研究了介导原发性耐药的机制 并检验JNK激活导致受体激活的假设 酪氨酸激酶Axl和下游ERK激活，并且该JNK-Axl-ERK轴介导原发性 对厄洛替尼耐药。在具体目标3中，我们检查了EGFR和EGFR的联合抑制的生物学效应。 TNF或JNK或Axl在临床前小鼠模型中检测适应性存活的中断 由EGFR抑制触发的信号传导将使具有原发性耐药的癌症转化为可以被治疗的癌症。 通过EGFR抑制有效治疗。由于EGFR和TNF抑制剂都在临床使用，因此这种方法 可以在患者身上快速测试。

项目成果

Ligand-Independent EGFR Signaling.

• DOI: 10.1158/0008-5472.can-15-0989
• 发表时间: 2015-09-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Guo G;Gong K;Wohlfeld B;Hatanpaa KJ;Zhao D;Habib AA
• 通讯作者: Habib AA

Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme.

• DOI: 10.1038/s41467-017-01392-9
• 发表时间: 2017-12-04
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Newman JP;Wang GY;Arima K;Guan SP;Waters MR;Cavenee WK;Pan E;Aliwarga E;Chong ST;Kok CYL;Endaya BB;Habib AA;Horibe T;Ng WH;Ho IAW;Hui KM;Kordula T;Lam PYP
• 通讯作者: Lam PYP