Understanding resistance in the HER2-HER3 tumor drive

了解 HER2-HER3 肿瘤驱动中的耐药性

• 批准号: 8578421
• 负责人: Mark M Moasser
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-22 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578421
• 关键词: Antibodies; BRAF gene; Biochemical; Clinical; Complex; Data; Development; Dimerization; Disease; Docking; Drug resistance; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Epithelial; Event; Exposure to; Extracellular Domain; Failure; Family; Foundations; Generations; Growth; HER2 inhibition; Immunologics; Ligands; Link; Lobe; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modality; Oncogenes; Oncogenic; Other Genetics; Output; Pathogenesis; Pathologic; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological; Regulation; Resistance; Role; Signal Transduction; Site; Solid; Structure; Surface; Tail; Testing; Therapeutic; Therapeutic Index; Transactivation; Tyrosine-Kinase Oncogenes; Up-Regulation; Work; base; cancer cell; clinical efficacy; drug development; effective therapy; in vivo; inhibitor/antagonist; insight; kinase inhibitor; leukemia; malignant breast neoplasm; melanoma; mutant; next generation; overexpression; public health relevance; receptor; response; small molecule; tumor; tumorigenic

DESCRIPTION (provided by applicant): The endeavor to treat HER2-amplified cancers through the inactivation of HER2 has proven more difficult than anticipated. The clinical activities of HER2 kinase inhibitors are weak, and better results with HER2 antibodies occur without the disruption of signaling, likely through immunologic mechanisms. The endeavor to inactivate the oncogenic function of HER2 awaits deeper mechanistic insights. Our work has highlighted the critical role of its partner HER3. Although kinase-inactive, HER3 is a functionally active and requisite partner of HER2 in this disease, and its dynamic regulation by a complex downstream network topology can upregulate HER2-HER3 signaling output 100-fold, undermining the efficacies of all forms of HER2 or HER3-targeted therapies. Effective suppression of the functionally relevant HER2-HER3 tumor driver requires deeper insights into the mechanism of signal generation in the pathologic state of HER2 overexpression. We have conducted a structure-function biochemical analysis of HER2-HER3 transactivation, specifically in the state of HER2 overexpression, revealing deeper insights into the mechanism of signal generation in this disease state. We find that the constitutive phosphorylation of HER3 occurs through interactions that do not require extracellular domain (ECD) activation or dimerization, or even proximity, defying the well described mechanisms for normal physiological signaling in this receptor family. However, HER2-HER3 activation does require kinase domain (KD) interactions, which in lieu of ECD-driven proximation events, are stoichiometrically driven by massive HER2 expression seen in these tumors. The evidence reveals functions in the HER3 KD including a function in its c-lobe as an allosteric activator of HER2 KD, a function in its n-lobe surface pocket, a function in the HER2 KD allosteric receiver site, and an unexpected requirement for the HER2 c-tail in promoting HER3 signaling. These data suggest that the plethoras of ECD-targeting approaches being pursued in the biotech sector are unlikely to yield highly effective therapies for HER2-amplified cancers. Rather it redirects this endeavor towards a focus on targeting kinase domain functions. In the next few years of this project we propose to establish the relevance of these findings to the in vivo tumorigenic growth of HER2- amplified breast cancers. In the first aim we will determine whether the described ligand and ECD-independent constitutive HER2-HER3 signal is the actual driver of tumorigenic growth in vivo. The impact of proximity restricting therapeutic modalities will also be tested. In the second aim we will test several newly discovered strategies targeting the KDs of HER2 and HER3 in the treatment of HER2-amplified cancers in vivo. In the third aim we will explore the more vaguely defined role of the HER2 and HER3 c-tails as either simple signaling substrates or functionally more involved in oligomerization and signal generation. These studies will define the rate-limiting steps for signal generation and tumorigenic growth in cancer cells driven by HER2 overexpression, laying the foundation for the development of highly effective therapies for HER2-amplified cancers.

描述（由申请人提供）：事实证明，通过灭活HER2来治疗HER2放大癌症的努力比预期的要困难得多。 HER2激酶抑制剂的临床活性较弱，而HER2抗体的结果更好，而没有信号传导的中断，这可能是通过免疫学机制。使HER2的致癌功能灭活的努力正在等待更深的机械见解。我们的工作强调了其伴侣Her3的关键作用。尽管激酶不活跃，但HER3在功能上是 HER2在这种疾病中的积极和必要的合作伙伴以及其通过复杂的下游网络拓扑的动态调节可以上调HER2-HER3信号输出100倍，从而破坏了所有形式的HER2或HER3靶向疗法的效率。有效抑制功能相关的HER2-HER3肿瘤驱动器需要更深入地了解HER2过表达的病理状态下信号产生的机理。 我们已经对HER2-HER3反式激活进行了结构功能生化分析，特别是在HER2过表达状态下，揭示了对这种疾病状态信号产生机理的更深入的见解。我们发现，HER3的组成型磷酸化是通过不需要细胞外域（ECD）激活或二聚化甚至接近性的相互作用而发生的，这违背了该受体家族中正常生理信号传导的精心描述的机制。然而，HER2-HER3激活确实需要激酶结构域（KD）相互作用，而代替ECD驱动的接近事件，它是由在这些肿瘤中看到的大量HER2表达驱动的。证据揭示了HER3 KD的功能，其中包括其C-Lobe中的功能，作为HER2 KD的变构激活剂，其N-Lobe表面袋中的功能，HER2 KD变构接收器位点的功能，以及HER2 C-Tail在促进HER3信号传导中的意外需求。这些数据表明，在生物技术部门采用的大量ECD靶向方法不太可能为HER2扩增的癌症产生高效的疗法。相反，它将这一努力重新定向到靶向激酶域功能。在该项目的接下来的几年中，我们建议确定这些发现与HER2-扩增乳腺癌的体内肿瘤生长的相关性。在第一个目的中，我们将确定所描述的配体和与ECD无关的构型HER2-HER3信号是体内肿瘤生长的实际驱动力。还将测试限制治疗方式的接近性限制的影响。在第二个目标中，我们将测试针对HER2和HER3 KD的几种新发现的策略，以治疗体内HER2扩增的癌症。在第三个目的中，我们将探讨HER2和HER3 C-Tails的更含糊其定义的作用，因为简单的信号底物或功能上更多地参与了寡聚和信号产生。这些研究将定义信号的限速步骤 由HER2过表达驱动的癌细胞中的产生和致瘤性生长为开发HER2扩增的癌症的高效疗法奠定了基础。