Molecular mechanism of EGFR heterodimerization: inhibition by a peptidomimetic

 描述（由申请人提供）：本研究项目的长期目标是了解表皮生长因子受体（EGFR）细胞外结构域（ECD）中异源二聚化在癌症中的作用，并研究新型肽模拟物对其的抑制作用，以探索产生靶向治疗药物的策略。短期目标是了解人表皮生长因子受体2（HER2）结构域IV的作用，靶向结构域IV的热点以抑制EGFR的蛋白质-蛋白质相互作用，并研究其在肺癌中的意义。在肺癌中，非小细胞肺癌（NSCLC）是最常见的，并且是全世界癌症死亡的主要原因。肺癌患者的预后很差，生存率约为一年，使其成为最不了解的癌症类型之一。EGFR在包括NSCLC在内的多种人类肿瘤中高度表达。大约18 - 33%的NSCLC肿瘤显示HER2过表达，表明HER2在NSCLC中的重要性。已知蛋白质HER2与其他EGFR相互作用并形成二聚体/异聚体。阻断HER2与其他EGFR的蛋白质-蛋白质相互作用最终导致控制细胞生长，因此对肺癌患者具有治疗价值。已经设计了一种肽模拟物分子，其特异性结合HER2蛋白并抑制EGFR蛋白的二聚化过程。这种方法是新颖的，因为设计的小分子不仅破坏EGFR-HER2二聚化，而且破坏HER2-HER3二聚化。EGFR和HER2的共表达与肺癌患者的总生存率显著缩短相关。因此，靶向HER2并抑制EGFR：HER2和HER2：HER3二聚化将对HER2过表达的肺癌产生显著影响。肽模拟物分子如何与HER2结合并改变HER2介导的信号传导的确切机制尚不清楚。用于体内给药的设计分子的稳定性尚未表征。因此，我们建议详细描述这种新设计的化合物与HER2蛋白结合的机制及其对细胞生长的异源二聚化、磷酸化和下游信号传导的影响。将研究以下目标。1)优化化合物的体内稳定性。2)了解EGFR的蛋白质-蛋白质相互作用的分子机制，开发的化合物的抑制作用及其对下游信号的影响。3)使用肺癌模型评价优化化合物的体内治疗功效。我们期望这个项目的结果将证实抑制的重要性 通过结合HER2胞外结构域的肽模拟物的二聚化。这类靶向EGFR信号传导多个通路的抑制剂将对目前较低的肺癌患者生存率产生影响。所描述的研究项目还为本科生提供了研究机会，并有助于在校园内创建生物医学教育活动。

 DESCRIPTION (provided by applicant): The long-term objective of this research project is to understand the role of heterodimerization in extracellular domains (ECD) of epidermal growth factor receptors (EGFRs) in cancer and to investigate its inhibition by novel peptidomimetics to explore strategies to generate targeted therapeutics. The short-term goals are to understand the role of domain IV of human epidermal growth factor receptor 2 (HER2), target the hot spot of domain IV to inhibit the protein-protein interactions of EGFRs, and study the implications of this in lung cancer. Among the lung cancers, non-small-cell lung cancer (NSCLC) is the most common and is a leading cause of cancer deaths worldwide. The prognosis of patients with lung cancer is poor, with a survival rate around one year, making it one of the least understood cancer types. EGFR are highly expressed in a variety of human tumors, including NSCLC. Approximately 18-33% of NSCLC tumors show HER2 overexpression, suggesting the importance of HER2 in NSCLC. The protein HER2 is known to interact with other EGFRs and form dimers/heteromers. The blockade of protein-protein interactions of HER2 with other EGFRs ultimately leads to control of cell growth and, hence, has therapeutic value for lung cancer patients. A peptidomimetic molecule has been designed that specifically binds to HER2 protein and inhibits the dimerization process of EGFR proteins. This approach is novel because the small molecule designed disrupts not only EGFR-HER2 dimerization but also HER2-HER3 dimerization. The coexpression of EGFR and HER2 has been associated with a significantly shortened overall survival rate of lung cancer patients. Thus, targeting HER2 and inhibiting EGFR:HER2 and HER2:HER3 dimerization will have a significant impact on HER2- overexpressed lung cancer. The exact mechanism of how the peptidomimetic molecule binds to HER2 and alters the HER2-mediated signaling is not well understood. The stability of the designed molecules for in vivo administration has not been characterized. We therefore propose to characterize details of the mechanism of binding of this newly designed compound to HER2 protein and its resulting effect on heterodimerization, phosphorylation, and downstream-signaling for cell growth. The following objectives will be investigated. 1) To optimize the compound for in vivo stability. 2) To understand the molecular mechanism of protein-protein interactions of EGFRs, its inhibition by the compounds developed, and its effect on downstream signaling. 3) To evaluate the therapeutic efficacy of an optimized compound in vivo using a lung cancer model. We expect that the results from this project will verify the importance of inhibition of dimerization by a peptidomimetic that binds to the HER2 extracellular domain. Such inhibitors that target multiple pathways of EGFRs signaling will have an impact on the survival rate of lung cancer patients, which is low at present. The research project described also provides research opportunities for undergraduate students and helps to create biomedical educational activities on campus.