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Overcoming drug resistance using small molecule activators of protein phosphatase 2A

使用蛋白磷酸酶 2A 小分子激活剂克服耐药性

基本信息

批准号：
10676204
负责人：
JENNIFER D. BLACK
金额：
$ 17.7万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-03 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676204
关键词：
Address Autophagocytosis Breast Cancer Patient CDK2 gene CDK4 gene CRISPR screen Cancer cell line Canis familiaris Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Line Cell Proliferation Cell Survival Cells Chemoresistance Clinic Clinical Trials Complex Cyclin D1 Cyclin-Dependent Kinase Inhibitor Cyclins Down-Regulation Drug resistance FDA approved G1 Phase Genetic Genetic Transcription Genotoxic Stress Head and Neck Squamous Cell Carcinoma Holoenzymes Human Immunodeficient Mouse Investigation Knock-out Link Maintenance Malignant Neoplasms Mediating Mitogens Mus Mutation Nature Non-Small-Cell Lung Carcinoma Normal Cell Oncogenic Organoids Patients Pharmaceutical Preparations Pharmacy (field)Phenotype Phosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Proteolysis Publishing Rattus Replication Initiation Research Personnel Resistance Role Seminal Signal Transduction Testing Therapeutic Toxic effect Translations Tumor Suppression Tumor Suppressor Proteins Ubiquitin Up-Regulation Xenograft procedure anti-cancer antitumor agent antitumor effect biological systems cancer cell cancer type cell type follow-up genome-wide in vivo Model in vivo evaluation inhibitor mRNA Stability melanoma mouse model multicatalytic endopeptidase complex neoplastic cell novel novel therapeutics nutrient deprivation overexpression patient population pharmacologic preclinical study protein complex protein degradation resistance mechanism response retinoblastoma tumor suppressor sensor small molecule targeted cancer therapy therapeutic target tumor tumorigenesis ubiquitin-protein ligase uncontrolled cell growth

项目摘要

Uncontrolled cell proliferation resulting from aberrant activity of cell cycle proteins is a hallmark of cancer. Overexpression of the mitogen sensor cyclin D1 is among the most frequent abnormalities in tumors, enhancing the activity of cyclin dependent kinases 4 and 6 (CDK4/6) to drive G1→S phase progression and promote cell survival and chemoresistance. Increased expression of D-type cyclins is required not only for tumorigenesis but also for tumor maintenance and progression. Thus, aberrant cyclin D-CDK4/6 activity represents an actionable target for cancer therapy and D-type cyclin function is among the top therapeutic targets for cancer management. Inhibitors of CDK4/6 activity have shown promise in the clinic and palbociclib, abemaciclib, and ribociclib are FDA-approved for use in patients. Several hundred clinical trials are currently ongoing to evaluate the antitumor effects of these agents in a broad spectrum of cancer types. However, the therapeutic promise of CDK4/6 inhibitors is dampened by inevitable emergence of resistance. Recent seminal studies have identified a novel mechanism of resistance to these agents mediated by deficiency of autophagy and beclin 1 regulator 1 (AMBRA1), an E3 ligase adaptor and master regulator of cyclin D1, D2, and D3 protein stability. Loss or mutation of AMBRA1 is seen in a significant subset of human cancers, in association with poor patient survival. AMBRA1 deficiency promotes the accumulation of D-type cyclins, a hyperproliferative phenotype, and tumorigenesis, while reducing the sensitivity of tumor cells to all three FDA-approved CDK4/6 inhibitors. Evidence that upregulation of D-type cyclins and the formation of non-canonical cyclin D-CDK2 and p27-cyclin D-CDK4 complexes underpins resistance to these agents forms the basis of this proposal. Strategies are proposed to explore the mechanism-driven application of Small Molecule Activators of PP2A (SMAPs) for overcoming resistance to CDK4/6 inhibitors in the context of AMBRA1 deficiency. SMAPs are a novel class of antitumor agents that selectively activate a subset of PP2A holoenzymes for potent tumor suppression in a variety of cancer types. This project builds on our discovery that SMAPs potently downregulate cyclins D1, D2 and D3 in all cell types tested. Importantly, SMAPs act as AMBRA1-independent D-type cyclin ‘degraders,’ promoting rapid proteolysis of these molecules via a proteasome-dependent mechanism that remains functional following loss of AMBRA1. Based on these findings, we hypothesize that combining CDK4/6 inhibitor treatment with a SMAP ‘D-type cyclin degrader’ will enhance antitumor activity and reverse resistance to CDK4/6 inhibitors driven by AMBRA1 deficiency. Proof-of-concept studies will be performed in two Specific Aims: (1) Explore the effects of combining CDK4/6 inhibitors and SMAPS in the context of AMBRA1-deficiency, and (2) Evaluate the effects of SMAP- CDK4/6 inhibitor combinations in tumor models in vivo. Importantly, in addition to addressing consequences of AMBRA1-deficiency, our proof-of-concept findings are anticipated to be broadly applicable to tumors harboring increased levels of D-type cyclins and aberrant CDK activity resulting from other tumor-associated alterations.

细胞周期蛋白活性异常导致的细胞增殖失控是癌症的一个标志。有丝分裂原感受器细胞周期蛋白d1的过度表达是肿瘤中最常见的异常之一，细胞周期蛋白依赖性蛋白依赖性激酶4和6的活性在→细胞周期中的作用生存和化疗耐药性。D型细胞周期蛋白的高表达不仅在肿瘤的发生中，而且在肿瘤发生中也是必需的对肿瘤的维持和发展也有帮助。因此，细胞周期蛋白D-CDK4/6的异常活性代表了一种可操作的肿瘤治疗的靶点和D-型细胞周期蛋白功能是癌症治疗的首要治疗靶点之一。 CDK4/6活性的抑制剂在临床上显示出良好的前景，Palbociclib、abemaciclib和riociclib是 FDA批准用于患者。目前正在进行数百项临床试验，以评估这种抗肿瘤药物这些药物在广泛的癌症类型中的作用。然而，CDK4/6的治疗前景不可避免地会出现耐药性，从而抑制了抑制剂的作用。最近的开创性研究确定了一部小说自噬和Beclin-1调节因子1缺陷介导的药物耐药机制 (AMBRA1)，一个E3连接酶适配器和细胞周期蛋白D1、D2和D3蛋白稳定性的主要调节因子。丢失或突变 AMBRA1基因在人类癌症的一个重要亚群中被发现，与患者较差的生存有关。AMBRA1 缺乏促进D型细胞周期蛋白的积累，而D型细胞周期蛋白是一种高度增殖的表型，并促进肿瘤的发生降低肿瘤细胞对FDA批准的所有三种CDK4/6抑制剂的敏感性。有证据表明，上调 D型细胞周期蛋白与非正则细胞周期蛋白D-CDK2和p27-细胞周期蛋白D-CDK4复合体的形成对这些药物的抵抗构成了这一提议的基础。提出了一些策略，以探索 PP2A小分子激活剂(SMAPs)在抗病机制中的应用 CDK4/6抑制剂在AMBRA1缺乏的背景下。SMAP是一类新型的抗肿瘤药物选择性地激活PP2A全酶的一个子集，在各种癌症类型中有效地抑制肿瘤。这个项目建立在我们的发现基础上，SMAP在所有类型的细胞中都能有效地下调细胞周期蛋白D1、D2和D3 测试过。重要的是，SMAP作为AMBRA1非依赖的D-型周期蛋白“降解物”，促进蛋白质的快速降解通过蛋白酶体依赖的机制，该机制在AMBRA1丢失后仍具有功能。基于这些发现，我们假设将CDK4/6抑制剂治疗与SMAP的D型周期相结合降解剂将增强抗肿瘤活性并逆转AMBRA1驱动的CDK4/6抑制剂的耐药性缺乏症。概念验证研究将在两个具体目标下进行：(1)探索组合的效果 CDK4/6抑制剂和SMAPS在AMBRA1缺乏的背景下，以及(2)评估SMAP-1的作用。体内肿瘤模型中的CDK4/6抑制剂组合。重要的是，除了解决以下问题的后果之外 AMBRA1缺乏，我们的概念验证结果预计将广泛适用于包含其他肿瘤相关改变导致D型细胞周期蛋白水平升高和CDK活性异常。