CDK2 and Cancer: Mechanisms and Opportunities

CDK2 与癌症：机制和机遇

基本信息

批准号：
9189712
负责人：
Bruce E Clurman
金额：
$ 40.98万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-04 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189712
关键词：
Abnormal Cell Biochemical Breast Cancer therapy CDK2 gene CDK4 gene Cell Cycle Cell Cycle Regulation Cell division Cells Chemotherapy-Oncologic Procedure Cyclin-Dependent Kinases DNA DNA Damage DNA Repair DNA biosynthesis Exhibits Failure Future Genes Genomic Instability Genotype Goals Human Knock-in Knock-in Mouse Link Malignant Neoplasms Mediating Mediator of activation protein Methods Modality Modeling Molecular Mus Mutation Normal Cell Oncogenic Pathway interactions Phosphorylation Phosphotransferases Physiological Proliferating Proteomics Role S Phase S Phase Arrest Signal Pathway Stress Therapeutic Therapeutic Index Tumor Suppression base biological adaptation to stress cancer cell cancer therapy chemotherapy expectation gene repair genome integrity in vivo inhibitor/antagonist insight killings mouse model neoplastic novel novel therapeutics prevent public health relevance response treatment strategy tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The realization that nearly all cancers have mutations that disrupt cell cycle control led to the expectation that cell cycle-directed therapy, particulary against the cyclin-dependent kinases (CDKs), would revolutionize cancer therapy. However, while the promise of this approach is nearing fruition through the use of CDK4/6 inhibitors, it has been less successful with CDK2, a kinase with central roles in quiescence, DNA replication, and DNA damage. CDK2 is thought to mediate many oncogenic signaling pathways and because its activity is abnormally high in cancer, most therapeutic approaches seek to inhibit CDK2. Instead, we seek to utilize CDK2 activity as a therapeutic modality rather than as a target for inhibition. Normal cells tightly regulate CDK2, and its inhibitory phosphorylation by Wee1 is a particularly important control in the contexts of replication stress and DNA damage. Indeed, CDK2 inhibitory phosphorylation is essential for a successful replication stress response, and the lack thereof during S-phase arrest causes catastrophic replication stress failure and irreparable DNA damage. The goals of this proposal are to utilize novel models and approaches to understand the functions of CDK2 and its inhibitory phosphorylation, and to apply these insights to exploit CDK2-induced replication stress failure to kill cancer cells. Aim 1's objectiv is to gain new understanding into how inhibitory phosphorylation and CDK2 activity regulate replication stress, DNA damage, and tumorigenesis. The first subaims employ targeted CDK2 mutations in human cells to study known mechanisms that may link CDK2 inhibitory phosphorylation to replication stress failure. The next set of subaims focuses on new mechanisms connecting CDK2 to DNA damage and replication stress control. Finally, we will use endogenous CDK2AF knockin mice to determine the role of CDK2 inhibitory phosphorylation in tumor suppression. By combining physiologic human and murine models with biochemical and proteomic methods, we hope to make fundamental advances into CDK2's normal and neoplastic functions. Aim 2 will determine if CDK2-driven replication stress can be used to repurpose chemotherapy that transiently inhibits S-phase into agents that kill cancer cells. Several features of cancer cells suggest that induced replication stress failure may exhibit the required therapeutic index, including their abnormally high proliferative rates and CDK2 activity, and the presence of oncogenic mutations that exacerbate CDK2- driven replication stress failure. This aim has two objectives: 1) to identify the molecular features that render cancers most sensitive to this approach, and 2) to establish mouse models to optimize and validate the concept of harnessing CDK2-driven replication stress as chemotherapy. If successful, these studies will provide new insights into CDK2 and cancer, and form the basis for future trials of using CDK2-driven replication stress failure to treat cancer.

描述（通过应用程序证明）：几乎所有破坏周期控制的癌症帽突变导致了CE LL周期定向的治疗，特别是针对Cyclin依赖性激酶（CDKS）的癌症Apporoch正在接近果实。 CDK2的成功率较小，这是一种在静止中的中心作用，DNA复制和DNA损伤将CDK2用作抑制型的terapeiTIC模态。利用新颖的模型和方法来了解CDK2及其其IT is抑制剂磷酸化的功能，并将洞察力应用于利用CDK2-IIM 1的objectiv是为了获得新的了解，以获得新的了解，以获得新的理解抑制性磷酸化和CDK2活性重复应力，DNA损害，DNA损害，DNA损害，DNA损害，DNA损害，DNA损害，DNA损害，DNA损害，DNA抑制作用，DNA抑制作用，DNA抑制作用，DNA磷酸化和抑制作用和肿瘤中的2个突变。我们的模型具有蛋白质方法，希望将基本进步纳入CDK2的正常和肿瘤功能。所需的治疗指数，其异常高的增殖率和CDK2活性加剧了CDK2驱动的复制应力故障。这些研究将优化和验证利用CDK2驱动的Essful的概念，将为CDK2和癌症提供新的见解，并形成使用CDK2驱动的复制应激不足以使癌症的基础试验的基础试验。