Identifying CDK4 and CDK6 substrates in cancers and cancer therapy

鉴定癌症和癌症治疗中的 CDK4 和 CDK6 底物

基本信息

批准号：
8958740
负责人：
Bruce E Clurman
金额：
$ 22.97万
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：
2015-07-01 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This application seeks to identify substrates of cyclin D-dependent kinases with critical roles in carcinogenesis and cell cycle-based cancer therapy. Mutations in the genes that control the cell cycle are among the most common genetic changes in cancer cells. Although many cell cycle proteins are implicated in cancers, the cyclin D-dependent kinases, CDK4 and CDK6, are fundamentally linked to carcinogenesis. Mutations that deregulate CDK4/6 activity are common in tumors, and CDK4/6 activity is critical for tumor cell maintenance. The essential roles of CDK4/6 in tumorigenesis stimulated the development of pharmacologic CDK4/6 inhibitors that may finally realize the promise of cell cycle-based cancer therapy. However, unlike other CDKs, which phosphorylate many substrates, very few CDK4/6 substrates are known. Indeed, almost all previous work has focused on the Retinoblastoma protein family, and the paucity of other known substrates has limited insights into the mechanisms of CDK4/6- associated cancer and therapy targeting these kinases. Despite the need to identify the CDK4/6 substrates relevant for tumorigenesis and therapy, numerous technical challenges have impeded efforts to identify these proteins. We have developed proteomic methods utilizing ATP analog-sensitive (AS) CDKs and substrate thiophosphorylation that enable us to efficiently identify CDK substrates, and have implemented this approach, termed in situ substrate detection, so as to closely mimic the physiologic environment of CDK substrate phosphorylation. We will now apply these methods to identify CDK4/6 substrates in cancers, and our preliminary studies have demonstrated their ability to detect endogenous and novel CDK6 substrates. This application's goal is to apply these innovative proteomic methods to identify novel CDK4/6 substrates that contribute to tumorigenesis, as well as to evaluate the efficacy of CDK4/6 inhibitors. If successful, this research will define new activities of CDK4/6 that may drive carcinogenesis, will enable future mechanistic studies of CDK4/6-associated cancer and pharmacologic CDK4/6 inhibitors, and may lead to new therapeutic targets.

描述（通过应用程序证明）：该应用旨在鉴定细胞周期的癌症治疗中的癌细胞疗法。，细胞周期蛋白D依赖性激酶，CDK4和CDK6 NESIS，过度调节CDK4/6活性在肿瘤中很常见，CDK4/6活性对于CDK4/6的肿瘤细胞在肿瘤中的维持作用至关重要但是，与其他CDK磷酸化的抑制剂最终可能是基于细胞周期的癌症治疗的希望对CDK4/6相关的癌症的机制有限，针对这些激酶的癌症和症状与肿瘤发生和治疗相关，许多技术挑战都妨碍了这些开发的蛋白质组学方法，利用ATP敏感的蛋白质组学方法CDK和底物硫代磷酸化使我们能够充满cdk底物，并实施了THYSTU底物检测，以便与生理学紧密相关。底座。该应用的目标是识别肿瘤发生的新型CDK4/6底物，以评估CDK4/6抑制剂的功效。，将使CDK4/6-6相关癌症和药理学CDK4/6抑制剂AD的未来机械研究成为新的治疗靶标。