The role of USP27X-Cyclin D1 axis in HER2 Therapy Resistant Breast Cancer

USP27X-Cyclin D1 轴在 HER2 治疗耐药乳腺癌中的作用

• 批准号: 10658373
• 负责人: Boyko S Atanassov
• 金额: $ 40.02万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-26 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658373
• 关键词: Ablation; Acceleration; Affect; Alleles; Antibody-drug conjugates; Biochemical; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; CDK4 gene; CRISPR/Cas technology; Cancer Model; Cancer Patient; Cancer cell line; Cell Line; Cell Proliferation; Cells; Clinical; Cyclin D1; Data; Dedications; Deubiquitinating Enzyme; Deubiquitination; Development; Drug Targeting; Drug resistance; ERBB2 gene; Engineering; Enzymes; Epidermal Growth Factor Receptor; Family; Fostering; Gene Expression Regulation; Genetic Transcription; HER2 inhibition; Hand; Histones; Human; LoxP-flanked allele; Malignant Neoplasms; Mediating; Molecular; Molecular Analysis; Mus; Pathway interactions; Patients; Phenotype; Process; Proteins; Recurrence; Regulation; Resistance; Role; Tamoxifen; Testing; Therapeutic Intervention; Trastuzumab; Tumor Escape; Tumorigenicity; Tyrosine Kinase Inhibitor; Ubiquitin; Work; Xenograft Model; cancer cell; cancer survival; cell growth; clinically relevant; druggable target; genetic approach; improved; in vivo; inducible Cre; inhibitor; insight; malignant breast neoplasm; member; mouse model; neoplastic cell; novel; overexpression; patient prognosis; resistance mechanism; response; small hairpin RNA; targeted agent; targeted treatment; therapeutic target; therapy resistant; treatment response; tumor; tumor growth; tumor xenograft; tumorigenesis; ubiquitin isopeptidase; ubiquitin-specific protease

PROJECT SUMMARY/ABSTRACT Overexpression of Cyclin D1 (CCND1) is recognized as a major resistance mechanism to HER2 targeting agents. Patients with CCND1 amplification have the worst response to trastuzumab-containing therapy, and CCND1 overexpression is enough to render cancer cells insensitive to HER2 inactivation. Furthermore, tumors that evade HER2 targeted therapy by reducing HER2 expression rely on CCND1 overexpression and are extremely sensitive to its ablation. Thus, targeting CCND1 is a promising strategy for overcoming resistance to HER2-targeting agents in breast cancer patients. Although CCND1 itself is not a druggable target, this protein has a rapid turnover, and its steady-state level in cells is tightly regulated by ubiquitin-mediated degradation. Perturbation of CCND1 deubiquitination accelerates its degradation. We have recently discovered a novel, previously uncharacterized deubiquitinating enzyme – USP27X, whose higher expression significantly correlates with poor survival of HER2 positive breast cancer patients. Importantly, our studies identify USP27X as a critical regulator of CCND1 protein stability in HER2 therapy-resistant breast cancer cells. Ablation of USP27X severely reduces xenograft tumor growth and significantly increases cell sensitivity to HER2 and CDK4/6 inhibitors. We hypothesize that USP27X can be a key therapeutic target in HER2 therapy-resistant or recurrent breast cancer through CCND1 degradation. This project focuses on understanding the functions of USP27X in CCND1 regulation and elucidating the roles of this deubiquitinating enzyme in cancer development and progression. We will utilize several engineered cell lines as well as a novel and clinically relevant mouse model carrying a conditional Usp27X allele to 1) Elucidate the molecular mechanism underlying the reduced CCND1 steady-state levels in USP27X ablated cells 2) Determine how the loss of USP27X will affect tumor development and progression in vivo, and 3) Define how abrogation of USP27X activity alters the therapeutic response of HER2 therapy-resistant cells to HER2 inhibition. USP27X is a druggable target, and our studies will illuminate new avenues for therapeutic intervention in HER2 therapy-resistant and CCND1 dependent cancers. Although there are no USP27X specific inhibitors currently available, the studies proposed in this project are essential for establishing this deubiquitinating enzyme as a drug target as they will provide a rationale for developing USP27X specific inhibitors.

项目摘要/摘要 细胞周期蛋白D1（CCND1）的过表达被认为是对HER2靶向的主要耐药机制 剂. CCND1扩增的患者对含曲妥珠单抗的治疗反应最差， CCND1过表达足以使癌细胞对HER2失活不敏感。此外，肿瘤 通过减少HER2表达来逃避HER2靶向治疗依赖于CCND1过表达， 对它的消融非常敏感因此，靶向CCND1是一种有希望的克服耐药性的策略。 乳腺癌患者中的HER 2靶向药物。虽然CCND1本身不是药物靶点，但这种蛋白质 具有快速周转，其在细胞中的稳态水平受到泛素介导的降解的严格调节。 干扰CCND1去泛素化加速其降解。我们最近发现了一本小说， 先前未表征的去泛素化酶-USP27X，其较高表达显著相关 HER2阳性乳腺癌患者的生存率很低。重要的是，我们的研究将USP27X确定为关键的 在HER2治疗抗性乳腺癌细胞中CCND1蛋白稳定性的调节剂。USP27X严重消融 减少异种移植肿瘤生长并显著增加细胞对HER2和CDK4/6抑制剂的敏感性。我们 假设USP27 X可以是HER2治疗抗性或复发性乳腺癌中关键治疗靶点 CCND1降解。本项目的重点是了解CCND1中USP27X的功能 调节和阐明这种去泛素化酶在癌症发展和进展中的作用。我们 将利用几种工程化细胞系以及一种新的和临床相关的小鼠模型， 条件性Usp27X等位基因，以1）阐明CCND1稳态降低的分子机制 2）确定USP27X的损失将如何影响肿瘤发展， 体内进展，和3）定义USP27X活性的消除如何改变HER2的治疗反应 治疗抗性细胞对HER2抑制。USP27X是一个可药用的目标，我们的研究将阐明新的 HER2治疗抗性和CCND1依赖性癌症的治疗干预途径。虽然 目前没有可用的USP27X特异性抑制剂，本项目中提出的研究对于以下方面至关重要： 建立这种去泛素化酶作为药物靶点，因为它们将为开发USP27X提供理论基础。 特异性抑制剂