Ron/EGFR interactions and therapeutic resistance in head and neck cancers

描述（由申请人提供）：过去20年的大量数据强烈支持表皮生长因子受体（EGFR）在头颈部鳞状细胞癌（HNSCC）中的重要作用。几家制药公司已经开发了EGFR抑制剂用于治疗这种疾病。虽然这些药物在临床试验中取得了一些早期成功，但反应并不像人们希望的那样戏剧性。因此，迫切需要更多的反应分子预测因子。最近的数据表明，EGFR和罗恩之间存在潜在的串扰。我们还发现过表达罗恩不仅反式激活EGFR，而且还调节其信号传导，使得EGFR抑制剂不再发挥其最大作用。此外，我们发现罗恩在一些原发性HNSCC中以高水平表达，并且罗恩+HNSCC更可能具有磷酸化EGFR。基于这些早期结果，我们提出以下假设：罗恩功能性地与EGFR相互作用，赋予HNSCC更具侵袭性的疾病表型。我们提出了两个具体目标来检验我们的假设：（1）我们将确定罗恩在原发性HNSCC中的患病率，并将其表达与预后相关联。(2)我们将研究同时表达高水平罗恩和EGFR的鳞状细胞癌细胞系是否对EGFR抑制剂的作用更难治。在目标1中，我们将使用三种分子方法确定原发性HNSCC中的罗恩和EGFR表达谱;然后，我们将进行相关性分析以确定高罗恩表达是否指示更具侵袭性的疾病特征和较差的存活率。在目标2中，我们将进行细胞生物学和生化分析，以进一步了解罗恩与EGFR的功能相互作用。我们将测试这种相互作用是否以EGFR抑制剂不再抑制其信号传导并发挥其最大作用的方式调节EGFR。我们的应用程序具有以下潜在影响。(1)本项目可能将罗恩作为HNSCC的潜在治疗靶点;（2）罗恩也可能是HNSCC的候选预后生物标志物。公共卫生相关性：我们建议了解两种癌症蛋白质EGFR和罗恩之间的相互作用。这些实验不仅解决了一些EGFR抑制剂没有产生显著结果的潜在原因;他们还将检查一种新的分子标记物罗恩对头颈部癌症的预后价值。

DESCRIPTION (provided by applicant): Ample data over the last 20 years strongly support an important role of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas (HNSCC). Several pharmaceutical companies have developed EGFR inhibitors for the treatment of this disease. While there have been some early success of these drugs in clinical trials, the response is not as dramatic as one would like. Thus, additional molecular predictors for response are urgently needed. Recent data suggested that there is potential cross talk between EGFR and Ron. We also discovered that overexpressing Ron not only transactivates EGFR, but also modulates its signaling such that the EGFR inhibitors can no longer exert their maximal effects. In addition, we found that Ron is expressed at high levels in some primary HNSCCs and that Ron+ HNSCCs are more likely to have phosphorylated EGFR. Based on these early results, we formulate the following hypothesis: Ron functionally interacts with EGFR to confer a more aggressive disease phenotype in HNSCC. We propose to test our hypothesis with two specific aims: (1) We will determine the prevalence of Ron in primary HNSCCs and correlate its expression with prognosis. (2) We will investigate if squamous cell carcinoma cell lines that express high level of both Ron and EGFR are more refractory to the action of EGFR inhibitors. In aim 1, we will determine Ron and EGFR expression profiles in primary HNSCCs using three molecular methods; then, we will perform correlation analysis to determine if high Ron expression is indicative of more aggressive disease features and poor survival. In aim 2, we will perform cell biology and biochemical analyses to further understand the functional interaction of Ron with EGFR. We will test if such interaction modulates EGFR in such a way that EGFR inhibitors can no longer inhibit its signaling and exert their maximal effects. Our application has the following potential impact. (1) This project may identify Ron as a potential therapeutic target fo HNSCC; (2) Ron may also be a candidate prognostic biomarker for HNSCC. PUBLIC HEALTH RELEVANCE: We propose to understand the interaction between two cancer proteins, EGFR and Ron. The experiments not only address a potential reason why some EGFR inhibitors have not produced dramatic results; they will examine the prognostic value of a new molecular marker, Ron, for head and neck cancers.