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(PI3K)通路是最常见的去调节信号之一 人类癌症中的级联反应，几乎调控人类肿瘤发生的方方面面，包括启动， 进展和转移性扩散。丝氨酸/苏氨酸蛋白激酶AKT将PI3K信号转导至 与恶性肿瘤相关的过多的细胞反应，包括细胞的增殖和生长， 生存、细胞运动和新陈代谢。尽管为了解码PI3K/AKT的功能而进行了广泛的努力 癌症中的信号转导，以及许多小分子抑制剂的开发，目的是阻断一个或多个 到目前为止，在这个途径中有更多的酶，对PI3K或AKT抑制的强大治疗反应仍然存在 难以捉摸。因此，迫切需要确定以前未意识到的与以下各项相关的漏洞 PI3K/AKT通路成瘾。在过去的二十年里，我们的实验室一直走在 关于调节PI3K下游AKT的发现，以及识别AKT通过 介导与恶性肿瘤相关的细胞表型的信号传递。此应用程序构建在我们的 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途径成瘾相关的脆弱性。在建议的 项目，我们将把我们的愿景集中在三个主要工作领域：1)由Genetic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的靶点 它将基因打靶与质谱学和功能验证结合在一起。我们还将使用新的基因 重现AKT过度激活并评估靶向治疗敏感性的小鼠模型；2)新 针对AKT的化学探测器和屏幕：我们已经产生了第一个同类降解剂或PROTAC 有效且特异地降解AKT，并优于目前所有的AKT抑制剂。我们将用这本小说 针对癌症中的AKT途径的探针。我们将进行合成致命的CRISPR筛查来揭开 当与PI3K和AKT抑制剂结合时，将细胞抑制反应转化为细胞毒性反应的靶点；3) PI3K/AKT对蛋白质糖基化的调节：我们发现了一种全新的机制，通过它可以 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 内质网应激的诱导。这是第一次将癌基因加成与合成碳水化合物联系起来。 新陈代谢，我们将用功能性糖组分来探索。拟议的研究不仅建立在我们的 他们还强调，迫切需要对多效性机制有详细的新见解。 它们控制着癌症中的PI3K和AKT信号。我们的发现将提供一种综合的、机械性的 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 这些脆弱性最终将导致开发新的癌症治疗机会。