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

基本信息

批准号：
10677761
负责人：
Alex Toker
金额：
$ 97.51万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10677761
关键词：
AKT Signaling Pathway AKT inhibition Area CRISPR screen Cell Proliferation Cellular Metabolic Process Chemicals Cytostatics Development Endoplasmic Reticulum Enzymes FRAP1 gene Gene Combinations Gene Targeting Genetic Goals Growth Factor Hematologic Neoplasms Human Interruption Laboratories Lesion Link Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Pathway Oncogenes Oncogenic PIK3CG gene 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 insight mouse model novel novel therapeutics protein folding response small molecule inhibitor targeted treatment treatment response tumor initiation tumor progression tumorigenesis virtual

项目摘要

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 靶点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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States.

DOI：
10.1158/0008-5472.can-22-0423
发表时间：
2023-01-18
期刊：
Cancer research
影响因子：
11.2
作者：
通讯作者：

Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.

DOI：
10.1371/journal.pgen.1009876
发表时间：
2021-11
期刊：
PLoS genetics
影响因子：
4.5
作者：
Madsen RR;Erickson EC;Rueda OM;Robin X;Caldas C;Toker A;Semple RK;Vanhaesebroeck B
通讯作者：
Vanhaesebroeck B

Can Improved Use of Biomarkers Alter the Fate of PI3K Pathway Inhibitors in the Clinic?

DOI：
10.1158/0008-5472.can-21-2035
发表时间：
2021-12-15
期刊：
Cancer research
影响因子：
11.2
作者：
Erickson EC;Toker A
通讯作者：
Toker A

The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia.

KRAS-G12D 突变导致 B 细胞急性淋巴细胞白血病代谢脆弱性

DOI：
10.1016/j.isci.2022.103881
发表时间：
2022-03-18
期刊：
iScience
影响因子：
5.8
作者：
Xu Y;Fang H;Chen Y;Tang Y;Sun H;Kong Z;Yang F;Kirschner-Schwabe R;Zhu L;Toker A;Xiao N;Zhou BS;Li H
通讯作者：
Li H

PI3K signaling through a biochemical systems lens.