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 扩增癌症的努力比预期更加困难。 HER2 激酶抑制剂的临床活性较弱，而 HER2 抗体可能会通过免疫机制在不干扰信号传导的情况下产生更好的结果。灭活 HER2 致癌功能的努力有待更深入的机制见解。我们的工作凸显了其合作伙伴 HER3 的关键作用。尽管 HER3 不具有激酶活性，但它在功能上是一种 HER2 在这种疾病中是 HER2 的活跃且必要的伙伴，其通过复杂的下游网络拓扑进行动态调节可以将 HER2-HER3 信号输出上调 100 倍，从而破坏所有形式的 HER2 或 HER3 靶向疗法的功效。有效抑制功能相关的 HER2-HER3 肿瘤驱动因素需要更深入地了解 HER2 过表达病理状态下信号产生的机制。 我们对 HER2-HER3 反式激活（特别是在 HER2 过表达状态下）进行了结构-功能生化分析，揭示了对该疾病状态下信号生成机制的更深入见解。我们发现 HER3 的组成型磷酸化是通过不需要细胞外结构域 (ECD) 激活或二聚化甚至接近的相互作用发生的，这违背了该受体家族中正常生理信号传导的良好描述的机制。然而，HER2-HER3 激活确实需要激酶结构域 (KD) 相互作用，而不是 ECD 驱动的邻近事件，而是由这些肿瘤中出现的大量 HER2 表达按化学计量驱动。证据揭示了 HER3 KD 中的功能，包括其 c 叶中作为 HER2 KD 变构激活剂的功能、其 n 叶表面袋中的功能、HER2 KD 变构受体位点中的功能，以及对 HER2 KD 变构受体位点的意外要求。 HER2 c-tail 促进 HER3 信号转导。这些数据表明，生物技术领域追求的大量 ECD 靶向方法不太可能为 HER2 扩增的癌症产生高效的治疗方法。相反，它将这一努力转向关注靶向激酶结构域功能。在该项目的未来几年中，我们建议确定这些发现与 HER2 扩增乳腺癌体内致瘤性生长的相关性。第一个目标是确定所描述的配体和不依赖于 ECD 的 HER2-HER3 信号是否是体内致瘤生长的实际驱动因素。邻近限制治疗方式的影响也将得到测试。在第二个目标中，我们将测试几种新发现的针对 HER2 和 HER3 KD 的策略在体内治疗 HER2 扩增癌症的过程中。在第三个目标中，我们将探索 HER2 和 HER3 c 尾的更模糊定义的作用，作为简单的信号底物或在功能上更多地参与寡聚化和信号生成。这些研究将定义信号的速率限制步骤 HER2 过度表达驱动癌细胞的产生和致瘤性生长，为开发针对 HER2 扩增癌症的高效疗法奠定了基础。