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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 Cyclin D1 (CCND1) 的过度表达被认为是 HER2 靶向的主要耐药机制 CCND1 扩增的患者对含曲妥珠单抗的治疗反应最差，并且 CCND1 过度表达足以使癌细胞对 HER2 失活不敏感。通过减少 HER2 表达来逃避 HER2 靶向治疗的药物依赖于 CCND1 过度表达，并且是因此，针对 CCND1 是克服耐药性的一种有前途的策略。乳腺癌患者中的 HER2 靶向药物虽然 CCND1 本身不是药物靶标，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。 CCND1 去泛素化的扰动加速了它的降解。以前未表征的去泛素化酶 – USP27X，其较高的表达与 HER2 阳性乳腺癌患者的生存率较差，重要的是，我们的研究将 USP27X 确定为关键。 HER2 治疗耐药乳腺癌细胞 CCND1 蛋白稳定性的调节剂 USP27X 严重消融。显着减少异种移植肿瘤的生长并增加细胞对 HER2 和 CDK4/6 抑制剂的敏感性。 USP27X 可以成为 HER2 治疗耐药或复发性乳腺癌的关键治疗靶点通过 CCND1 降解该项目重点了解 USP27X 在 CCND1 中的功能。调节并阐明这种去泛素化酶在癌症发生和进展中的作用。将利用几种工程细胞系以及一种新型且临床相关的小鼠模型，该模型携带条件 Usp27X 等位基因 1) 阐明减少 CCND1 稳态的分子机制 USP27X 消融细胞中的水平 2) 确定 USP27X 的缺失将如何影响肿瘤的发展和体内进展，以及 3) 定义 USP27X 活性的废除如何改变 HER2 的治疗反应对 HER2 抑制产生耐药性的细胞是一个可药物靶标，我们的研究将阐明新的方向。 HER2 治疗耐药性和 CCND1 依赖性癌症的治疗干预途径目前尚无 USP27X 特异性抑制剂，本项目中提出的研究对于建立这种去泛素化酶作为药物靶点，因为它们将为开发 USP27X 提供理论依据特异性抑制剂。