Targeting SMURF2 as a novel therapy for EGFR driven tumors

靶向 SMURF2 作为 EGFR 驱动肿瘤的新疗法

• 批准号: 8699027
• 负责人: Dipankar Ray
• 金额: $ 27.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699027
• 关键词: Affect; Binding; CBL gene; Cancer cell line; Cell Death; Cell Survival; Cells; Colorectal; Combined Modality Therapy; Data; Development; Down-Regulation; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; Epithelial; Foundations; Goals; Growth; Head and Neck Cancer; Head and neck structure; Human; Individual; Ligase; Link; Lung; Lung Adenocarcinoma; Lysine; Malignant Neoplasms; Mediating; Messenger RNA; Modification; Molecular; Mono-S; Mutate; Mutation; Patients; Pattern; Phosphotransferases; Play; Post-Translational Protein Processing; Proline; Proteins; RNA; Radiation therapy; Radio; Reporting; Resistance; Role; Small Interfering RNA; Testing; Therapeutic; Tumor Burden; Ubiquitination; base; cancer cell; cancer therapy; cell growth; chemotherapy; cofactor; cohort; head and neck cancer patient; improved; inhibitor/antagonist; insight; killings; knock-down; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; peptidomimetics; protein degradation; receptor; research study; response; scaffold; small hairpin RNA; small molecule; success; tumor; tumor xenograft; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Over-expression of epidermal growth factor receptor (EGFR) drives several cancers including lung, head & neck (H&N) and colorectal, where targeting EGFR kinase activity has produced definite but limited successes. Based on previous reports and our preliminary studies, we hypothesize that the effectiveness of an anti-EGFR therapy can be greatly increased by facilitating EGFR protein degradation as opposed to simple inhibition of its kinase activity. Towards this goal, we have identified a novel interaction between EGFR and a HECT type ubiquitin ligase, Smad ubiquitination regulatory factor 2 (SMURF2), which is critical for EGFR protein stability and by targeting SMURF2 we can efficiently degrade EGFR to kill EGFR addicted cancer cells and stop the growth of human tumor xenografts. We have also discovered significant correlation of expression of the two proteins at the RNA and protein levels in a large group of lung and H&N cancer patients. The main goal of this proposal is to understand the molecular interaction between EGFR and SMURF2 in upper aerodigestive cancers and to develop a novel therapeutic strategy by inducing EGFR degradation via targeting SMURF2. We believe that by down-regulating SMURF2, EGFR will be more vulnerable to degradation, independent of its overexpression or mutation status in cancer and such a strategy will be therapeutically more potent as it can physically abolish EGFR. We propose to achieve these goals through 3 specific aims: In aim 1, we hypothesize that certain lysine residues are critical for SMURF2 mediated protein ubiquitination, responsible for EGFR protein stability. Specific aim 1 is to determine whether SMURF2-mediated ubiquitination can covalently modify certain lysine residues on EGFR to stabilize it from undergoing degradation. In specific aim 2, we hypothesize that by down-regulating SMURF2 via shRNA, we can reduce the tumor burden as individual therapy or can sensitize tumor cells that are resistant to currently available chemo-/radiotherapy. Specific aim 2 is to explore the therapeutic potential of SMURF2 targeting as a novel approach in upper aerodigestive cancer treatment. In aim 3, we hypothesize that EGFR and SMURF2 interacts in sequence specific manner in association with certain cofactors. Specific aim 3 we will identify the domain(s) of EGFR and cofactors that are assisting in its stable interaction and protein modification by SMURF2. Results obtained from this study will help us establish a novel approach targeting EGFR, independent of a drug resistant EGFR mutation by altering its ubiquitination status via SMURF2 targeting. We anticipate that successful completion of this project will not only provide a better mechanistic insight exploring the roles of ubiquitination in EGFR protein stability, it will also provide a strong foundation for the development of peptidomimetic scaffold or small molecule inhibitor, which can disrupt EGFR-SMURF2 interaction to kill cancer cells and will be beneficial for certain patients.

描述（由申请人提供）：表皮生长因子受体（EGFR）的过表达驱动了几种癌症，包括肺癌、头颈癌（H&N）和结肠直肠癌，其中靶向EGFR激酶活性已经产生了明确但有限的成功。基于以前的报告和我们的初步研究，我们假设，抗EGFR治疗的有效性可以大大增加促进EGFR蛋白降解，而不是简单地抑制其激酶活性。为了实现这一目标，我们已经确定了EGFR和HECT型泛素连接酶Smad泛素化调节因子2（SMURF 2）之间的新型相互作用，其对于EGFR蛋白稳定性至关重要，并且通过靶向SMURF 2，我们可以有效地降解EGFR以杀死EGFR成瘾的癌细胞并停止人肿瘤异种移植物的生长。我们还发现在一大组肺癌和H&N癌患者中，这两种蛋白质在RNA和蛋白质水平上的表达具有显著相关性。该提案的主要目标是了解EGFR和SMURF 2在上呼吸消化道癌症中的分子相互作用，并通过靶向SMURF 2诱导EGFR降解来开发新的治疗策略。我们认为，通过下调SMURF 2，EGFR将更容易降解，而与其在癌症中的过表达或突变状态无关，并且这种策略在治疗上将更有效，因为它可以物理地消除EGFR。我们建议通过3个具体目标来实现这些目标：在目标1中，我们假设某些赖氨酸残基对于SMURF 2介导的蛋白泛素化至关重要，负责EGFR蛋白的稳定性。具体目标1是确定SMURF 2介导的泛素化是否可以共价修饰EGFR上的某些赖氨酸残基，以稳定其免于降解。在具体目标2中，我们假设通过shRNA下调SMURF 2，我们可以作为个体治疗来降低肿瘤负荷，或者可以使对目前可用的化疗/放疗具有抗性的肿瘤细胞敏感。具体目标2是探索SMURF 2靶向作为上呼吸消化道癌症治疗新方法的治疗潜力。在目标3中，我们假设EGFR和SMURF 2以序列特异性方式与某些辅因子相互作用。具体目标3：我们将鉴定EGFR的结构域和辅助因子，这些结构域和辅助因子通过SMURF 2帮助其稳定相互作用和蛋白质修饰。从这项研究中获得的结果将帮助我们建立一种新的方法靶向EGFR，通过SMURF 2靶向改变其泛素化状态，独立于耐药EGFR突变。我们预计，该项目的成功完成不仅将为探索泛素化在EGFR蛋白稳定性中的作用提供更好的机制见解，还将为开发肽模拟物支架或小分子抑制剂提供坚实的基础，这些支架或小分子抑制剂可以破坏EGFR-SMURF 2相互作用以杀死癌细胞，并对某些患者有益。