ErbB receptor homo- and hetero-dimerization

描述（由申请人提供）：该申请是对通知编号（NOT-OD-09-058）的回应：NIH宣布恢复法案资金可用于竞争性修订申请。受体酪氨酸激酶的ErbB家族的四个成员在许多人类癌症中是重要的。不幸的是，EGFR和ErbB 2靶向药物在许多癌症中的临床研究非常令人失望。最近的研究表明，ErbB 3，一种神经调节蛋白（NRG）受体，其激酶结构域被认为是无活性的，提供了大部分解释。尽管ErbB 2在癌症的引发和维持中发出促进细胞生长的信号，但它必须与ErbB 3形成NRG诱导的异二聚体才能做到这一点。ErbB 3促使乳腺癌患者逃避ErbB 2和EGFR靶向治疗。因此，ErbB 3信号传导对于ErbB 2（和EGFR）在细胞信号传导中的作用以及ErbB 2和EGFR靶向治疗的临床失败都是至关重要的。因此，有人认为，靶向ErbB 3是一个关键的治疗策略-尽管进展受到其明显缺乏激酶活性的阻碍（使其不清楚如何靶向受体）。在最近的研究中，我们已经证明ErbB 3确实具有显著的酪氨酸激酶活性。以前的研究未能检测到这种活性，反映了在这些早期报告发表时，对配体诱导的ErbB受体二聚化的理解相对缺乏。当正确激活时，纯化的ErbB 3被强烈地自磷酸化。这一发现为治疗性抑制一种以前认为不存在的重要激酶活性打开了大门。我们还解决了ErbB 3激酶结构域的晶体结构，这说明了这种激酶是如何激活的。该提案评估了ErbB 3激酶活性的信号重要性，并描述了开始寻找（和评估）ErbB 3特异性激酶抑制剂的方法。A.为了验证ErbB 3激酶活性对于乳腺癌细胞中的信号传导和逃避ErbB 2/EGFR靶向治疗至关重要的假设。B。建立体外定量分析ErbB 3激酶活性和抑制剂评估的方法。C.确定哪些现有的激酶抑制剂抑制ErbB 3，以便它们可以用于测试药理学ErbB 3抑制可以阻断ErbB信号传导和生长的原理。这一目标也将转向鉴定新的ErbB 3靶向激酶抑制剂。D.评估ErbB 3中激酶活性的结构基础。经济影响：宾夕法尼亚大学医学院对当地经济贡献巨大。2008年，该校创造了37，000个就业机会和54亿美元的区域经济活动，该地区训练有素的劳动力为840个开放的宾夕法尼亚大学员工研究职位提供了24，600多份申请。目前的提案将创造或保留2个新的工作岗位。 公共卫生相关性：成功完成我们提出的研究将导致产生新的ErbB 3靶向激酶抑制剂作为治疗药物，这将对赫赛汀或Tykerb治疗难治性乳腺癌患者的治疗产生直接和明确的影响。ErbB 3靶向药物与赫赛汀和/或Tykerb联合应用，可显著提高这些药物在各种不同方案中的缓解率。

DESCRIPTION (provided by applicant): The application is in response to Notice Number (NOT-OD-09-058): NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The four members of the ErbB family of receptor tyrosine kinases are important in many human cancers. Unfortunately, clinical studies with EGFR- and ErbB2-targeted agents in many cancers are very disappointing. Very recent work shows that ErbB3, a neuregulin (NRG) receptor with a kinase domain that is believed to be inactive, provides much of the explanation. Although ErbB2 signals to promote cell growth in the initiation and maintenance of cancers, it must form NRG-induced heterodimers with ErbB3 to do so. ErbB3 drives escape from ErbB2 and EGFR-targeted therapies in breast cancer. Thus, ErbB3 signaling is critical both for the role of ErbB2 (and EGFR) in cell signaling and for clinical failure of ErbB2 and EGFR-targeted therapies. Accordingly, it has been argued that targeting ErbB3 is a crucial therapeutic strategy - although progress is stymied by its apparent lack of kinase activity (leaving it unclear how to target the receptor). In very recent studies, we have shown that ErbB3 does have significant tyrosine kinase activity after all. The failure of previous studies to detect this activity reflects the relative lack of understanding of ligand-induced dimerization of ErbB receptors at the time those early reports were published. When activated correctly, purified ErbB3 is robustly autophosphorylated. This finding opens the door to therapeutic inhibition of an important kinase activity that was previously thought not to exist. We have also solved the ErbB3 kinase domain crystal structure, which illustrates how this kinase can be active. This proposal evaluates the signaling importance of ErbB3 kinase activity, and describes approaches to begin the search (and assessment) of ErbB3-specific kinase inhibitors. A. To test the hypothesis that ErbB3 kinase activity is critical for signaling in breast cancer cells and for escape from ErbB2/EGFR-targeted therapies. B. To develop in vitro assays for quantitative analysis of ErbB3 kinase activity and inhibitor assessment. C. To identify which existing kinase inhibitors inhibit ErbB3, so that they can be employed to test the principle that pharmacological ErbB3 inhibition can block ErbB signaling and growth. This Aim will also move towards identification of novel ErbB3-targeted kinase inhibitors. D. Assess the structural basis for kinase activity in ErbB3. Economic Impact: The University of Pennsylvania School of Medicine contributes substantially to the local economy. In 2008, the School created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain 2 new jobs. PUBLIC HEALTH RELEVANCE: Successful completion of our proposed research will lead to the generation of novel ErbB3-targeted kinase inhibitors as therapeutic agents, which would have a direct and clear impact on the treatment given to patients with breast cancer that is refractory to treatment with Herceptin or Tykerb. Inclusion of ErbB3-targeted agents with Herceptin and/or Tykerb should significantly improve the response rate to these drugs in a variety of different regimens.