Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer

摘要/摘要 在过去的十年中，研究已经开始揭示基因突变之间的几个直接联系 人类癌症和控制细胞代谢的基因。LKB1肿瘤抑制因子是丝氨酸/苏氨酸 在家族性癌症疾病Peutz-Jeghers综合征中，激酶突变失活，以及在~25% 在非小细胞肺癌中，使其成为这种癌症类型中第三常见的基因改变，这是 每年死于癌症的人数最多。13年前，Shaw实验室和其他人 发现LKB1直接磷酸化AMP激活的蛋白激酶的激活环 (AMPK)和12个相关的激酶。AMPK是一种丝氨酸/苏氨酸激酶，由LKB1在 细胞能量低的状态，如伴随营养物质损失的状态，尤其是葡萄糖和 氧气。AMPK是一种高度保守的能量感受器，可以恢复新陈代谢。 通过下调合成代谢生物合成的三磷酸腺苷在细胞和最终生物水平上的动态平衡 消耗过程(如蛋白质和脂肪的生物合成)，以及上调分解代谢的ATP恢复 过程(如自噬和脂肪酸氧化)。Shaw实验室在过去十年中的研究表明 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的直接底物，以及2)确定新的癌症治疗方法 基于他们对AMPK代谢和生长的限速节点的理解的方法 在低能量条件下内源利用。Shaw实验室使用了一些基因上的 非小细胞肺癌基因工程小鼠模型对新型癌症进行临床前研究 这笔赠款建立在他们过去十年积累的专业知识的基础上。三行 提出了研究的方向。首先，邵逸夫将利用蛋白质组学和基因技术方面的进展 实验室对具有或不具有完整LKB1的原发肿瘤进行磷酸化蛋白质组筛选以识别 肺内肿瘤抑制所需的相关靶点。这些事件将在基因上快速建模 细胞系，并最终在使用CRISPR的小鼠癌症模型中。第二，基于他们对 AMPK如何抑制生长，Shaw实验室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 一项提案寻求检查其他脂肪酸合成酶是否可能在 肺癌。第三，这项提案将探索AMPK及其靶点自噬激酶ULK1在 促进肿瘤细胞存活，特别是在治疗反应的背景下。总而言之，这些研究 强调需要深入了解该信令网络的分子布线以及如何 它与关键的细胞进程交互，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.