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.

磷脂酰肌醇3-激酶（PI 3 K）通路是最常见的失调信号通路之一， 级联在人类癌症，调节几乎所有方面的肿瘤发生在人类，包括启动， 进展和转移性播散。丝氨酸/苏氨酸蛋白激酶AKT将PI 3 K信号转导至 与恶性肿瘤相关的过多细胞反应，包括细胞增殖和生长， 存活、细胞运动和代谢。尽管针对PI 3 K/AKT的功能解码进行了广泛的努力， 许多小分子抑制剂被开发出来，目的是中断一种或多种信号传导。 由于该途径中存在更多的酶，迄今为止仍然存在对PI 3 K或AKT抑制的稳健的治疗反应 难以捉摸。因此，迫切需要查明以前未被认识到的与以下方面有关的脆弱性： PI 3 K/AKT通路成瘾。在过去的二十年里，我们的实验室一直处于领先地位， 关于PI 3 K下游AKT调节的发现，以及AKT 介导与恶性肿瘤相关的细胞表型的信号传递。此应用程序基于我们的 在破译PI 3 K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PI 3 K/AKT通路成瘾相关的脆弱性。拟议 项目，我们将集中我们的愿景在三个主要领域的工作：1）目标的PI 3 K/AKT定义的遗传 方法：我们将使用定义的CRISPR筛选来定义调节细胞表型的AKT靶点 将基因靶向与质谱和功能验证结合起来的联合收割机。我们还将使用新的基因 重现AKT过度活化并评估对靶向治疗敏感性的小鼠模型; 2）新的 针对AKT的化学探针和筛选：我们已经产生了第一个同类降解剂或PROTAC， 有效地和特异性地降解AKT，并优于所有目前的AKT抑制剂。我们会用这本小说 针对癌症中AKT通路的探针。我们将进行合成致命CRISPR筛选， 当与PI 3 K和AKT抑制剂组合时，将细胞抑制反应转化为细胞毒性反应的靶点; 3） 通过PI 3 K/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PI 3 K/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。这种机制的放松管制导致 诱导内质网应激。这是第一次鉴定出致癌基因与合成代谢碳水化合物的关系 我们将用功能性糖组学来探索代谢。拟议的研究不仅建立在我们的 他们还强调迫切需要获得详细的多效性机制的新见解 在癌症中控制PI 3 K和AKT信号传导。我们的发现将提供一个综合的， 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 这些弱点最终将导致癌症新治疗机会的发展。