Understanding CDK1 Function and Cancer Vulnerabilities

项目摘要/摘要 对侵袭性或转移性癌症进行精确治疗，同时提供更好的疗效承诺 毒性小，很少有持久的反应，只能适度延长患者的生命。少校 这些方法的局限性是癌细胞进化和替代信号通路可以补偿 靶向治疗阻断的通路，即多种可选的激活机制 EGFR/RAS/MAPK通路导致不同激酶串联作用的“重击鼹鼠”途径 抑制剂。细胞周期蛋白依赖性蛋白激酶(CDK)是一个保守的蛋白激酶家族，发挥着重要的作用 在调节真核细胞周期方面。CDK1与其活化亚单位Cyclin B一起发挥关键作用 在允许细胞进入有丝分裂中的作用，协调忠实的有丝分裂进程所需的事件和 染色体分离。据我们所知，CDK1/B活性对所有细胞的增殖和 没有其他途径可以绕过CDK1的要求。我们假设CDK1是一个理想的 导致细胞周期流产的特定致癌信号通路背景下的治疗靶点 程序，如细胞死亡或衰老，而非肿瘤细胞只被短暂地阻止。到目前为止， CDK1的特异性抑制剂还不存在，限制了我们发现CDK1潜在机制的能力 将抑制作为一种癌症治疗。我们实验室开发了一种新型的基因工程小鼠，使用了一种化学基因 这种方法允许我们在正常和癌基因转化的细胞中选择性和可逆地抑制CDK1， 或者在转基因肿瘤模型的背景下。我们的目标将定义CDK1通过什么机制引发 生长停滞和衰老(目标1)，调节未折叠蛋白反应(目标2)，以及CDK1如何 抑制和其他疗法最好结合起来阻止肿瘤生长(目标3)。我们带来了一个 在癌基因信号和细胞周期调节方面拥有创新研究记录的团队(Andrei Goga)； 擅长化学生物学和类比敏感蛋白(Kevin Shokat)；体内衰老研究(Anil Bhushan)和未折叠蛋白反应(UPR)调节机制方面的专业知识。我们假设 CDK1控制着以前未探索过的细胞过程，可用于肿瘤特异性 漏洞。这些发现将加速CDK1抑制剂在临床上的应用 人类癌症。

Project Summary/Abstract Precision therapies for aggressive or metastatic cancers, while offering the promise of greater efficacy and less toxicity, rarely achieve durable responses and only modestly extend a patient's life. The major limitation to these approaches is that cancer cells evolve and alternate signaling pathways can compensate for pathways blocked with targeted therapies, i.e. multiple alternative mechanisms to activate the EGFR/RAS/MAPK pathway lead to a "whack-a-mole" approach with serial treatment with different kinase inhibitors. Cyclin-dependent kinases (CDKs) are a conserved family of protein kinases that play a central role in regulating the eukaryotic cell cycle. CDK1 in conjunction with its activating subunit, Cyclin B, plays a critical role in permitting cells to enter mitosis, coordinates the events required for faithful mitotic progression and chromosome segregation. To our knowledge, CDK1/B activity is essential for all cells to proliferate and there are no alternative pathways to bypass the requirement for CDK1. We hypothesize that CDK1 is an ideal therapeutic target in the context of specific oncogenic signaling pathways which result in an abortive cell cycle program, such as cell death or senescence, while non-tumor cells are only transiently arrested. Until now, specific inhibitors of CDK1 have not existed, limiting our ability to discover the underlying mechanisms of CDK1 inhibition as a cancer therapy. Our lab developed a novel engineered mouse, using a chemical-genetic approach, that allows us to inhibit CDK1 selectively and reversibly in normal and oncogene transformed cells, or in the context of transgenic tumor models. Our aims will define the mechanisms through which CDK1 elicits growth arrest and senescence (Aim 1), regulates the unfolded protein response (Aim 2), and how CDK1 inhibition and other therapeutics can be best combined to block tumor growth (Aim 3). We bring together a team with a track record of innovative research in oncogene signaling and cell cycle regulation (Andrei Goga); expertise in chemical biology and analog-sensitive kinases (Kevan Shokat); in vivo studies of senescence (Anil Bhushan) and expertise in mechanisms of regulation of the unfolded protein response (UPR). We hypothesize that CDK1 controls previously unexplored cellular processes which can be exploited for tumor-specific vulnerabilities. Such discoveries will hasten the clinical translation of CDK1 inhibitors for a broad variety of human cancers.