Understanding CDK1 Function and Cancer Vulnerabilities

项目总结/摘要 针对侵袭性或转移性癌症的精确治疗，同时提供更高疗效的承诺 而且毒性较小，很少达到持久的反应，只能适度延长患者的生命。主要 这些方法的局限性是癌细胞的进化和替代信号通路可以补偿 用靶向治疗阻断的途径，即多种替代机制来激活 EGFR/RAS/MAPK通路导致不同激酶系列治疗的“打地鼠”方法 抑制剂的细胞周期蛋白依赖性激酶（Cyclin-dependent kinases，CDKs）是一类保守的蛋白激酶家族，在细胞周期调控中发挥重要作用 在调节真核细胞周期方面。CDK 1与其活化亚基细胞周期蛋白B一起，在细胞周期中起着关键的作用。 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， 染色体分离据我们所知，CDK 1/B活性对于所有细胞增殖和增殖都是必不可少的。 没有替代途径来绕过对CDK 1的需求。我们假设CDK 1是一个理想的 在导致细胞周期失败的特定致癌信号传导途径的背景下的治疗靶点 在某些情况下，肿瘤细胞的生长可能会受到抑制，例如细胞死亡或衰老，而非肿瘤细胞仅被短暂阻止。到目前为止， CDK 1的特异性抑制剂还不存在，限制了我们发现CDK 1潜在机制的能力 抑制作为癌症治疗。我们的实验室开发了一种新的工程小鼠，使用化学遗传学， 方法，使我们能够在正常和癌基因转化细胞中选择性和可逆地抑制CDK 1， 或在转基因肿瘤模型的情况下。我们的目标是确定CDK 1通过何种机制发挥作用， 生长停滞和衰老（目标1），调节未折叠蛋白反应（目标2），以及CDK 1 抑制剂和其它治疗剂可以最好地组合以阻断肿瘤生长（目的3）。我们汇集了一个 在癌基因信号传导和细胞周期调控方面具有创新研究记录的团队（Andrei Goga）; 化学生物学和类似物敏感激酶方面的专业知识（Kevan Shokat）;衰老的体内研究（Anil Bhushan）和未折叠蛋白反应（UPR）调节机制的专业知识。我们假设 CDK 1控制以前未探索的细胞过程，这些过程可以用于肿瘤特异性 漏洞这些发现将加速CDK 1抑制剂的临床转化， 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.