Understanding resistance to HER family tyrosine kinase inhibitors

了解 HER 家族酪氨酸激酶抑制剂的耐药性

• 批准号: 7261067
• 负责人: Mark M Moasser
• 金额: $ 32.97万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261067
• 关键词: Antibodies; Antineoplastic Agents; Cell surface; Chemosensitization; Clinical; Clinical Research; Cultured Cells; Data; Development; Dose; Drug Delivery Systems; Drug resistance; EGFR inhibition; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Equilibrium; Failure; Family; Family member; Feedback; Goals; Histologic; Human; In Vitro; Kinetics; Life; Link; Malignant Neoplasms; Mediating; Microvascular Permeability; Modality; Modeling; Molecular; Morphology; Nature; Neoplasms in Vascular Tissue; Oncogene Proteins; Oncogenes; Oncogenic; Paclitaxel; Pathway interactions; Perfusion; Permeability; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiologic pulse; Pre-Clinical Model; Proteasome Inhibitor; Protein Dephosphorylation; Protein Tyrosine Kinase; Proteins; Pulse taking; Refractory; Research; Research Personnel; Resistance; Role; Schedule; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Surface; Testing; Therapeutic; Thinking; Tyrosine Kinase Inhibitor; Vascular Permeabilities; Work; Xenograft Model; base; cancer therapy; chemotherapy; clinically relevant; drug sensitivity; in vivo; inhibitor/antagonist; knock-down; mouse model; neoplastic cell; oxidation; programs; research clinical testing; research study; response; small hairpin RNA; tumor; uptake

DESCRIPTION (provided by applicant): Oncogenic tyrosine kinases have proven to be promising targets for the development of highly effective anticancer drugs. However HER family tyrosine kinase inhibitors (TKIs) show only limited activity against HER2-driven cancers despite effective inhibition of EGFR and HER2 in vivo. The reasons for this are unclear. Signaling in trans is a key feature of this multimember family and an abundance of work from our lab and others has shown that TKI sensitivity in these tumors is mediated through the critically important PI3K/Akt pathway, which is driven predominantly through trans-phosphorylation of the kinase-inactive HER3. We have now discovered that although TKIs suppress EGFR and HER2 phosphorylation effectively, phosphorylation of the trans-target HER3 recovers after a transient inhibition and continues to drive PI3K/Akt signaling. This appears to be due to a compensatory shift in the HER3 phosphorylation-dephosphorylation equilbrium steady state and is driven largely by redistribution of HER3 to the cell surface. Our overall goal is to understand the molecular mechanisms that underlie HER3 resistance and to re-evaluate the utility of HER TKIs in the treatment of HER2-driven cancers. In aim 1 we propose to confirm the critical role of HER3 in tumor drug resistance by establishing a HER3 siRNA in vivo knock-down model. In addition to this proof-of- principle experiment, we will test several more readily translatable pharmacologic strategies to suppress HER3 signaling and overcome TKI resistance. The transient effects of current TKIs may be clinically relevant, since when used in a pulse dosing schedule preceding chemotherapy, we find that they have a previously unrealized chemosensitization potential. Preliminary data suggests that this chemosensitization is mediated through transient effects on tumor vasculature and possible enhanced tumor delivery of chemotherapeutics. In aim 2 we propose to study this hypothesis using radiologic and histologic studies of tumor vascular perfusion, permeability, and drug delivery. If they are found to support the hypothesis, the radiologic modalities will be translatable to our ongoing clinical studies of pulse chemosensitization. In the third aim, we seek to determine the molecular mechanisms by which HER3 redistributes to the cell surface and overcomes initial suppression by TKIs. Preliminary evidence suggests that Akt-driven negative feedback signaling directly or indirectly regulates HER3 localization. All experimental evidence suggests that certain cancers are driven by HER family oncoproteins, yet HER family TKIs have failed to deliver the promise of this oncogene hypothesis. We believe this is due to the previously unrealized short-lived nature of their effects. Through the proposed research program, we plan to develop treatment strategies to optimally use current HER family TKIs as transient inhibitors, and to develop much more effective therapies that more durably inhibit HER family signaling.

描述（由申请人提供）：致癌酪氨酸激酶已被证明是开发高效抗癌药物的有希望的靶标。然而，HER 家族酪氨酸激酶抑制剂 (TKI) 尽管在体内能有效抑制 EGFR 和 HER2，但对 HER2 驱动的癌症仅表现出有限的活性。其原因尚不清楚。反式信号传导是这个多成员家族的一个关键特征，我们实验室和其他实验室的大量工作表明，这些肿瘤中的 TKI 敏感性是通过至关重要的 PI3K/Akt 途径介导的，该途径主要是通过激酶失活 HER3。我们现在发现，尽管 TKI 能有效抑制 EGFR 和 HER2 磷酸化，但反式靶标 HER3 的磷酸化在短暂抑制后会恢复，并继续驱动 PI3K/Akt 信号传导。这似乎是由于 HER3 磷酸化-去磷酸化平衡稳态的补偿性变化，并且很大程度上是由 HER3 重新分布到细胞表面驱动的。我们的总体目标是了解 HER3 耐药性的分子机制，并重新评估 HER TKI 在治疗 HER2 驱动的癌症中的效用。在目标 1 中，我们建议通过建立 HER3 siRNA 体内敲低模型来证实 HER3 在肿瘤耐药性中的关键作用。除了这个原理验证实验之外，我们还将测试几种更容易转化的药理学策略，以抑制 HER3 信号传导并克服 TKI 耐药性。当前 TKI 的短暂效应可能具有临床相关性，因为当在化疗前用于脉冲给药方案时，我们发现它们具有以前未实现的化疗增敏潜力。初步数据表明，这种化学敏化是通过对肿瘤脉管系统的短暂影响以及可能增强化疗药物的肿瘤递送来介导的。在目标 2 中，我们建议利用肿瘤血管灌注、渗透性和药物输送的放射学和组织学研究来研究这一假设。如果发现它们支持这一假设，则放射学方式将可转化为我们正在进行的脉冲化学增敏临床研究。第三个目标是确定 HER3 重新分布到细胞表面并克服 TKI 最初抑制的分子机制。初步证据表明 Akt 驱动的负反馈信号直接或间接调节 HER3 定位。所有实验证据都表明某些癌症是由 HER 家族癌蛋白驱动的，但 HER 家族 TKI 未能实现这一癌基因假说的承诺。我们认为这是由于之前未意识到其影响的短暂性。通过拟议的研究计划，我们计划开发治疗策略，以最佳地使用当前的 HER 家族 TKI 作为瞬时抑制剂，并开发更有效的疗法，更持久地抑制 HER 家族信号传导。