Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes

项目2：摘要 指导这一建议的假设是错构瘤综合征基因(PTEN，LKB1，TSC1， TSC2)主要是重新连接新陈代谢，暴露了独特的漏洞。这个项目的重点是更好地 了解代谢易损性的分子和生化基础，并提供临床前数据 这将支持开发生物标记物驱动的临床试验，以评估此类药物在慢性阻塞性肺疾病患者中的应用。 生殖系或许多含有错构瘤综合征基因零星突变的肿瘤。我们有 在上一个资助期破译了每个哺乳动物蛋白激酶的最佳底物基序，并 制造了一种算法，可以让我们破译给定生物样本中哪些激酶是活跃的，哪些是不活跃的 基于无偏见的磷酸蛋白质组学。在这里，我们将重点介绍使用这种新方法来识别新的 以LKB1依赖的激酶为靶标的代谢酶。其具体目标是：1)定义关键激酶-- 细胞系和组织中错构瘤基因中底物相互作用的解除调控；2)定义代谢 细胞系和组织中错构瘤基因失控的脆弱性；以及3)定义AMPK如何控制 TFEB有助于错构瘤细胞的存活以及基于新的认识如何靶向肿瘤 这条路。

Project 2: Abstract The hypothesis guiding this proposal is that mutations in hamartoma syndrome genes (PTEN, LKB1, TSC1, TSC2) dominantly rewire metabolism exposing unique vulnerabilities. The focus of this project is to better understand the molecular and biochemical basis for the metabolic vulnerabilities and provide preclinical data that would support the development of biomarker driven clinical trials to evaluate such drugs in patients with germline or the many tumors containing sporadic mutations in hamartoma syndrome genes. We have decoded the optimal substrate motif for every single mammalian protein kinase in the last funding period and made an algorithm that allows us to decode which kinases are active or inactive in a given biological samples based on unbiased phospho-proteomics. Here we will focus on use of this new method to identify new metabolic enzymes targeted by LKB1-dependent kinases. The specific aims are: 1) Defining critical kinase- substrate interactions deregulated in hamartoma genes in cell lines and tissues; 2) Defining metabolic vulnerabilities deregulated in hamartoma genes in cell lines and tissues; and 3) Defining how AMPK control of TFEB contributes to the survival of hamartoma cells and how to target tumors based on new understanding of this pathway.