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

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.