CDK2 and Cancer: Mechanisms and Opportunities

CDK2 与癌症：机制和机遇

• 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
• 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

 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（由申请人提供）：认识到几乎所有癌症都具有破坏细胞周期控制的突变，导致预期细胞周期定向治疗，特别是针对细胞周期蛋白依赖性激酶（CDK）的治疗，将彻底改变癌症治疗。然而，虽然通过使用CDK 4/6抑制剂，这种方法的前景即将实现，但它 CDK 2是一种在静止、DNA复制和DNA损伤中起核心作用的激酶。CDK 2被认为介导许多致癌信号传导途径，并且由于其活性在癌症中异常高，因此大多数治疗方法寻求抑制CDK 2。相反，我们寻求利用CDK 2活性作为治疗方式，而不是作为抑制的靶点。正常细胞紧密调节CDK 2，并且其通过Wee 1的抑制性磷酸化在复制应激和DNA损伤的背景下是特别重要的控制。事实上，CDK 2抑制性磷酸化对于成功的复制应激反应是必不可少的，并且在S期停滞期间缺乏CDK 2抑制性磷酸化会导致灾难性的复制应激失败和不可修复的DNA损伤。该提案的目标是利用新的模型和方法来了解CDK 2及其抑制性磷酸化的功能，并应用这些见解来利用CDK 2诱导的复制应激失败来杀死癌细胞。 目的1的目的是获得新的理解，抑制性磷酸化和CDK 2活性如何调节复制应激，DNA损伤和肿瘤发生。第一个子目标是在人类细胞中采用靶向CDK 2突变来研究可能将CDK 2抑制性磷酸化与复制应激失败联系起来的已知机制。下一组子目标集中于将CDK 2与DNA损伤和复制应激控制联系起来的新机制。最后，我们将使用内源性CDK 2AF敲入小鼠来确定CDK 2抑制性磷酸化在肿瘤抑制中的作用。通过结合生理人类和小鼠模型与生物化学和蛋白质组学方法，我们希望对CDK 2的正常和肿瘤功能做出根本性的进展。 目的2将确定CDK 2驱动的复制应激是否可用于将短暂抑制S期的化疗重新用于杀死癌细胞的药物。癌细胞的几个特征表明，诱导的复制应激失败可能表现出 所需的治疗指数，包括其异常高的增殖率和CDK 2活性，以及存在加剧CDK 2驱动的复制应激失败的致癌突变。这一目标有两个目标：1）确定使癌症对这种方法最敏感的分子特征，2）建立小鼠模型以优化和验证利用CDK 2驱动的复制应激作为化疗的概念。如果成功，这些研究将为CDK 2和癌症提供新的见解，并为未来使用CDK 2驱动的复制应激失败治疗癌症的试验奠定基础。