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) 途径是最常失调的信号传导途径之一 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，包括起始、 进展和转移扩散。丝氨酸/苏氨酸蛋白激酶 AKT 将 PI3K 信号转导 与恶性肿瘤相关的大量细胞反应，包括细胞增殖和生长， 生存、细胞运动和新陈代谢。尽管为了解码 PI3K/AKT 的功能付出了巨大的努力 癌症中的信号传导，并且开发了多种小分子抑制剂，旨在中断一种或多种 该途径中存在更多酶，迄今为止仍保持对 PI3K 或 AKT 抑制的强大治疗反应 难以捉摸。因此，迫切需要识别以前未意识到的与以下相关的漏洞： PI3K/AKT 通路成瘾。二十年来，我们的实验室一直走在前沿 关于 PI3K 下游 AKT 调节的发现，以及确定 AKT 调节的机制 介导与恶性肿瘤相关的细胞表型的信号传递。该应用程序建立在我们的 破译 PI3K 和 AKT 在癌症中的贡献的集体经验，重点是发现、 识别和表征与 PI3K/AKT 通路成瘾相关的漏洞。在提议的 项目中，我们将把我们的愿景集中在三个主要工作领域：1）由遗传定义的 PI3K/AKT 目标 方法：我们将使用定义的 CRISPR 筛选来定义调节细胞表型的 AKT 靶标 将基因打靶与质谱和功能验证相结合。我们还将使用新的基因 重现 AKT 过度激活并评估对靶向治疗敏感性的小鼠模型； 2）小说 针对 AKT 的化学探针和筛选：我们已经生成了第一个同类降解剂或 PROTAC， 有效且特异性地降解 AKT，并且优于目前所有的 AKT 抑制剂。我们将使用这本小说 探针靶向癌症中的 AKT 通路。我们将进行合成致死性 CRISPR 筛选来发现 与 PI3K 和 AKT 抑制剂联合使用时，可将细胞抑制反应转变为细胞毒性反应； 3） PI3K/AKT 调节蛋白质糖基化：我们发现了一种全新的机制 生长因子和致癌信号通过 PI3K/AKT/mTOR 调节 N-糖基化途径， 内质网 (ER) 中蛋白质正确折叠所必需的。放松对这一机制的管制会导致 诱导 ER 应激。这是首次将癌基因添加与合成代谢碳水化合物联系起来 新陈代谢，我们将通过功能糖组学来探索。拟议的研究不仅建立在我们的基础上 他们还强调迫切需要获得有关多效性机制的详细新见解 控制癌症中的 PI3K 和 AKT 信号传导。我们的研究结果将提供一个综合的、机械的 了解致癌信号如何与细胞重编程相互作用并暴露癌症特异性 最终将导致开发新的癌症治疗机会。