Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer

解码并靶向癌症中的 LKB1-AMPK 信号通路

• 批准号: 10667573
• 负责人: Reuben Shaw
• 金额: $ 114.07万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667573
• 关键词: 5' -AMP-activated protein kinase; Acetyl-CoA Carboxylase; Autophagocytosis; Biochemical Pathway; Cancer Model; Cell Line; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Consumption; Disease; Enzyme Inhibitor Drugs; Enzymes; Event; Fatty Acids; Genes; Genetic Models; Genetically Engineered Mouse; Glucose; Grant; Growth; Hereditary Malignant Neoplasm; Homeostasis; Human; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Nutrient; Oxygen; Pathway interactions; Peutz-Jeghers Syndrome; Phosphorylation; Phosphotransferases; Play; Primary Neoplasm; Process; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteomics; Research; Role; STK11 gene; Serine; Signal Pathway; Signal Transduction; Starvation; Therapeutic; Tumor Promotion; Tumor Suppression; Tumor Suppressor Proteins; anticancer activity; cancer cell; cancer therapy; cancer type; drug metabolism; fatty acid oxidation; genetic technology; lipid biosynthesis; lipogenesis inhibitor; new therapeutic target; novel; preclinical study; preservation; programs; sensor; treatment response; tumor metabolism

Summary / Abstract Research over the past decade has begun to reveal several direct linkages between genes mutated in human cancer and genes that control cell metabolism. The LKB1 tumor suppressor is a serine/threonine kinase mutationally inactivated in the familial cancer disease Peutz-Jeghers Syndrome, as well as in ~25% of non-small cell lung cancers, making it the third most frequent gene altered in this cancer type, which is responsible for the most deaths by cancer each year. Thirteen years ago, the Shaw lab and others discovered that LKB1 directly phosphorylates the activation loop of the AMP-activated protein kinase (AMPK) and 12 related kinases. AMPK is a serine/threonine kinase that is activated by LKB1 under conditions of low cellular energy, such as those that accompany loss of nutrients, in particular glucose and oxygen. AMPK plays a highly conserved role as an energy sensor and acts to restore metabolic homeostasis on a cellular and ultimately organismal level by downregulating anabolic biosynthetic ATP- consuming processes (like protein and lipid biosynthesis), and upregulating catabolic ATP-restoring processes (like autophagy and fatty acid oxidation). Studies by the Shaw lab over the past decade have sought to: 1) understand the mechanistic basis for how AMPK reprograms growth and metabolism by decoding direct substrates of AMPK that mediate its downstream effects, and 2) identify new cancer therapy approaches based on their understanding of the rate-limiting nodes of metabolism and growth that AMPK endogenously utilizes under low energy conditions. The Shaw lab has used a number of genetically engineered mouse models of non-small cell lung cancer to perform preclinical studies with novel cancer metabolism drugs, and this grant builds upon their expertise accumulated over the past decade. Three lines of research are proposed. First, advances in proteomics and genetic technologies will be used by the Shaw lab to conduct phospho-proteome screens in primary tumors that are with or without intact LKB1 to identify relevant targets required for tumor suppression in lung. These events will be rapidly modeled genetically in cell lines and ultimately in murine cancer models using CRISPR. Second, based on their understanding of how AMPK inhibits growth, the Shaw lab has explored the use of direct inhibitors of the lipogenesis enzyme Acetyl-CoA carboxylase (ACC) and found broad anti-cancer activity in genetic models of lung cancer. This proposal seeks to examine whether other fatty acid synthesis enzymes may offer therapeutic windows in lung cancer. Third, this proposal will explore the role of AMPK and its target the autophagy kinase ULK1 in promoting tumor cell survival, particularly in the context of therapeutic response. Altogether, these studies emphasize the need to gain a deep understanding of the molecular wiring of this signaling network and how it interfaces with key cellular processes in order to reveal novel vulnerabilities that can be exploited to selectively kill cancer cells.

摘要 /摘要 在过去的十年中，研究开始揭示了突变的基因之间的几个直接联系 人类癌症和控制细胞代谢的基因。 LKB1肿瘤抑制剂是丝氨酸/苏氨酸 激酶在家族性癌症疾病PEUTZ-JEGHERS综合征中被灭活，以及约25％ 非小细胞肺癌的癌症，使其成为这种癌症类型中第三次最常见的基因，即 每年造成癌症死亡人数最多。十三年前，肖实验室和其他人 发现LKB1直接磷酸化AMP激活蛋白激酶的激活环 （AMPK）和12个相关激酶。 AMPK是一种丝氨酸/苏氨酸激酶，在LKB1下激活 低细胞能量的条件，例如伴随营养素损失的疾病，特别是葡萄糖和 氧。 AMPK作为能量传感器起着高度保守的作用，并起作用以恢复代谢 通过下调合成代谢生物合成ATP- 食用过程（例如蛋白质和脂质生物合成），并上调分解代谢的ATP-Restoring 过程（例如自噬和脂肪酸氧化）。 Shaw Lab在过去十年中的研究 试图：1）了解AMPK如何重新编程生长和代谢的机理基础 解码介导其下游效应的AMPK的直接底物，2）确定新的癌症治疗 方法是基于他们对AMPK的代谢和生长的限制限制节点的理解 在低能条件下内源使用。肖实验室使用了许多遗传学 非小细胞肺癌的工程小鼠模型，用于与新型癌症进行临床前研究 代谢药物和这笔赠款基于过去十年积累的专业知识。三行 提出了研究。首先，Shaw将使用蛋白质组学和遗传技术的进步 实验室在具有或没有完整lkb1的原发性肿瘤中进行磷酸化 - 蛋白质体筛选以识别 肺部抑制肿瘤所需的相关靶标。这些事件将在遗传上迅速建模 细胞系，最终使用CRISPR在鼠类癌模型中。第二，基于他们对 AMPK如何抑制生长，Shaw Lab探索了脂肪生成酶的直接抑制剂的使用 乙酰辅酶A羧化酶（ACC）发现肺癌遗传模型中的广泛抗癌活性。这 提案试图检查其他脂肪酸合成酶是否可以在 肺癌。第三，该提案将探讨AMPK及其目标的作用 促进肿瘤细胞存活，特别是在治疗反应的背景下。这些研究总共 强调需要深入了解该信号网络的分子布线以及如何 它与关键的蜂窝过程接口，以揭示可以利用的新漏洞 有选择地杀死癌细胞。