Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer

PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能

• 批准号: 10246864
• 负责人: Alex Toker
• 金额: $ 103.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10246864
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; AKT inhibition; Area; CRISPR screen; Cell Proliferation; Cellular Metabolic Process; Chemicals; Cytostatics; Development; Endoplasmic Reticulum; Enzymes; FRAP1 gene; Gene Targeting; Genetic; Goals; Growth Factor; Hematologic Neoplasms; Human; Interruption; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic Pathway; Oncogenes; Oncogenic; Pathway interactions; Phenotype; Phosphatidylinositols; Phosphotransferases; Protein Glycosylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Regulation; Signal Transduction; Solid; Validation; Vision; Work; addiction; carbohydrate metabolism; cell growth; cell motility; cytotoxic; endoplasmic reticulum stress; experience; genetic approach; glycosylation; inhibitor/antagonist; insight; mouse model; novel; novel therapeutics; protein folding; response; small molecule inhibitor; targeted treatment; treatment response; tumor initiation; tumor progression; tumorigenesis; virtual

The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently deregulated signaling cascades in human cancers, regulating virtually all aspects of tumorigenesis in humans, including initiation, progression and metastatic dissemination. The serine/threonine protein kinase AKT transduces PI3K signals to a plethora of cellular responses that are associated with malignancy, including cell proliferation and growth, survival, cell motility and metabolism. In spite of extensive efforts aimed at decoding the function of PI3K/AKT signaling in cancer, and a multitude of small molecule inhibitors developed and aimed at interrupting one or more enzymes in this pathway, robust therapeutic responses to PI3K or AKT inhibition have to date remained elusive. There is therefore an urgent need to identify previously unappreciated vulnerabilities associated with PI3K/AKT pathway addiction. Over the past two decades, our laboratory has been at the forefront of discoveries on the regulation of AKT downstream of PI3K, as well as identifying mechanisms by which AKT mediates signal relay to cellular phenotypes associated with malignancy. This application builds on our collective experience at deciphering the contribution of PI3K and AKT in cancer with emphasis at discovering, identifying and characterizing vulnerabilities associated with PI3K/AKT pathway addiction. In the proposed projects, we will focus our vision in three major areas of work: 1) targets of PI3K/AKT defined by genetic approaches: we will define targets of AKT that modulate cellular phenotypes using defined CRISPR screens that combine gene targeting with mass spectrometry and functional validation. We will also use new genetic mouse models that recapitulate AKT hyperactivation and evaluate sensitivity to targeted therapies; 2) novel chemical probes and screens targeting AKT: we have generated the first in-class degrader or PROTAC that potently and specifically degrades AKT, and out-performs all current AKT inhibitors. We will use this novel probe to target the AKT pathway in cancer. We will perform synthetic lethal CRISPR screens to uncover targets that when combined with PI3K and AKT inhibitors transform cytostatic responses to cytotoxic ones; 3) regulation of protein glycosylation by PI3K/AKT: we have uncovered an entirely new mechanism by which growth factor and oncogenic signaling through PI3K/AKT/mTOR modulates the N-glycosylation pathway, necessary for proper protein folding in the endoplasmic reticulum (ER). Deregulation of this mechanism leads to induction of ER stress. This is the first identification linking oncogene addition to anabolic carbohydrate metabolism, which we will explore with functional glycomics. The proposed studies not only build on our expertise, they also emphasize the urgent need to obtain detailed new insights into the pleiotropic mechanisms that govern PI3K and AKT signaling in cancer. Our findings will provide an integrated, mechanistic understanding of how oncogenic signaling interfaces with cellular reprogramming and expose cancer-specific vulnerabilities that would ultimately lead to the development of new therapeutic opportunities for cancer.

磷酸肌醇3-激酶（PI3K）途径是最常见的失控信号之一 人类癌症中的级联反应，几乎调节人类肿瘤发生的所有方面，包括启动， 进展和转移传播。丝氨酸/苏氨酸蛋白激酶Akt将PI3K信号传递到 与恶性肿瘤有关的大量细胞反应，包括细胞增殖和生长， 生存，细胞运动和代谢。尽管旨在解码PI3K/AKT的功能 癌症中的信号传导以及许多小分子抑制剂开发和旨在中断一个或 在此途径中，更多的酶，对PI3K或AKT抑制的强大治疗反应必须持续到 难以捉摸。因此，迫切需要确定与以前没有批准的漏洞 PI3K/AKT途径成瘾。在过去的二十年中，我们的实验室一直处于 关于PI3K下游AKT调节的发现，以及识别AKT的机制 介导信号继电器与与恶性肿瘤相关的细胞表型。此应用程序建立在我们的 在解密PI3K和AKT在癌症中的贡献方面的集体经验，重点是发现， 识别和表征与PI3K/AKT途径成瘾相关的漏洞。在提议中 项目，我们将把愿景集中在三个主要工作领域：1）遗传定义的PI3K/AKT目标 方法：我们将使用定义的CRISPR屏幕来定义AKT的目标，该目标可以调节蜂窝表型 将基因靶向与质谱和功能验证相结合。我们还将使用新的遗传 概括Akt过度激活并评估对靶向疗法的敏感性的小鼠模型； 2）小说 靶向AKT的化学探针和屏幕：我们已经生成了第一个课堂降级器或Protac 有力，专门降低AKT，并超过所有当前AKT抑制剂。我们将使用这本小说 探针以靶向癌症的AKT途径。我们将执行合成致命的CRISPR屏幕以发现 目标是与PI3K和Akt抑制剂结合使用，将细胞毒性反应转化为细胞毒性反应； 3） 通过PI3K/AKT调节蛋白质糖基化：我们已经发现了一种全新的机制 通过PI3K/AKT/MTOR的生长因子和致癌信号传导调节N-糖基化途径， 对于内质网中（ER）中适当的蛋白质折叠所必需的。这种机制的放松管制导致 诱导ER应力。这是将癌基因添加到合成代谢碳水化合物的第一个识别 代谢，我们将使用功能性糖化探索。拟议的研究不仅基于我们 他们还强调了迫切需要获得对多效机制的详细见解的迫切需要 控制癌症中的PI3K和AKT信号。我们的发现将提供一个集成的机械 了解如何与细胞重编程和暴露癌症特异性的致癌信号传导界面 最终导致癌症新的治疗机会的脆弱性。