Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer

总结/摘要 过去十年的研究已经开始揭示出， 人类癌症和控制细胞代谢的基因。LKB 1肿瘤抑制因子是丝氨酸/苏氨酸 家族性癌症Peutz-Jeghers综合征中突变失活的激酶，以及约25%的 在非小细胞肺癌中，它是第三个最常见的基因改变， 每年死于癌症的人数最多十三年前，肖氏实验室和其他实验室 发现LKB 1直接磷酸化AMP激活蛋白激酶的激活环 （AMPK）和12种相关激酶。AMPK是一种丝氨酸/苏氨酸激酶，其被LKB 1激活， 低细胞能量的状况，例如伴随营养物质损失的那些，特别是葡萄糖和 氧气AMPK作为能量传感器发挥高度保守的作用， 通过下调合成代谢生物合成ATP， 消耗过程（如蛋白质和脂质生物合成），并上调分解代谢ATP恢复 过程（如自噬和脂肪酸氧化）。肖氏实验室在过去十年的研究 试图：1）了解AMPK如何通过以下方式重新编程生长和代谢的机制基础： 解码介导其下游效应的AMPK直接底物，和2）鉴定新的癌症疗法 基于他们对代谢和生长的限速节点的理解，AMPK 在低能量条件下内源利用。肖氏实验室使用了一些基因 非小细胞肺癌的基因工程小鼠模型，以进行新型癌症的临床前研究 代谢药物，这项赠款建立在他们的专业知识积累在过去十年。三行 的研究提出。首先，肖氏夫妇将利用蛋白质组学和遗传技术的进步 实验室进行磷酸化蛋白质组筛选原发性肿瘤，有或没有完整的LKB 1，以确定 肺肿瘤抑制所需的相关靶点。这些事件将在基因上迅速建模， 细胞系，并最终在小鼠癌症模型中使用CRISPR。第二，根据他们对 AMPK如何抑制生长，Shaw实验室已经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），并在肺癌的遗传模型中发现了广泛的抗癌活性。这 一项提案旨在研究其他脂肪酸合成酶是否可以为糖尿病患者提供治疗窗口。 肺癌第三，本提案将探讨AMPK及其靶点自噬激酶ULK 1在 促进肿瘤细胞存活，特别是在治疗反应的情况下。总之，这些研究 强调需要深入了解这个信号网络的分子布线以及如何 它与关键的细胞过程相互作用，以揭示可被利用的新漏洞， 选择性地杀死癌细胞。

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.