Project Summary/Abstract Project 1: Identifying new therapeutic avenues to selectivelytarget tumors with uncontrolled mTORC1 activ ation While targeted cancer therapies offer great promise, the wiring and plasticity of oncogenic signaling networks makes primary or acquired resistance virtually inevitable. Many of the most common oncogenes and tumor suppressors underlying human cancers impinge on mTOR complex 1 (mTORC1) regulation as a shared downstream target, resulting in aberrant activation of mTORC1 in over half of all cancers. Sustained mTORC1 signaling has emerged as a major mechanism of resistance to targeted cancer therapies. However, mTOR inhibitors such as rapamycin have limited use on their own for inducing tumor regression. We hypothesize that the inability of tumor cells to properly regulate mTORC1 signaling, which is known to promote a broad program of anabolic metabolism, renders them more susceptible to inhibition of specific cellular pathways and processes. We will use a combination of hypothesis-driven and unbiased approaches to identify the major vulnerabilities stemming from uncontrolled mTORC1 activity. We take advantage of the high degree of evolutionary conservation within the mTOR network and perform cross-species synthetic lethal (SL) screens that initiate in Drosophila and end in mammalian tumor models to identify robust genetic relationships selectively influencing tumor cell survival. The project integrates high-throughput screening technologies in reductionist systems (Perrimon laboratory) with mechanistic characterization in cell and tumor models (Manning laboratory). Within the broader context of this P01, the project is discovery-based and fundamental to the overarching goal of understanding and targeting the signaling network that connects the hamartoma syndrome tumor suppressors (TSC1, TSC2, PTEN, LKB1, and NF1). The novel candidate targets and mechanisms revealed through our project will serve as a key point of integration for all 3 projects.