Over 30% of all incurable lung adenocarcinomas have a KRAS mutation and, despite the impressive advances in targeted therapies over past several years, no approved or highly effective targeted therapy exists for this subset of lung cancers. Recently, we have used comprehensive approaches, including interrogation of genetically-engineered mouse models (GEMMs), to examine the efficacy of novel therapeutic strategies for KRAS-mutant lung cancers. For example, 2 promising treatments are the combination of PI3K inhibitors with MEK inhibitors and docetaxel with MEK inhibitors, both which have activity in KRAS-mutant lung cancers. However, these approaches are not effective in the subset of KRAS-mutant cancers with concomitant loss of LKB1 (kinase that phosphorylates AMPK), suggesting these cancers may require unique targeted therapies. We found that, while Kras/p53-mutant cancers - which are susceptible to these therapies - had strong activation of MEK-ERK pathway, the resistant Kras/Lkb1-mutant lung cancers had strikingly minimal engagement of this pathway. This finding provides mechanistic insight to the primary resistance of Kras/Lkb1 lung cancers to combination therapies with MEK inhibitors. However, recent findings suggest that cancers with LKB1 deficiency have altered metabolic wiring that could potentially be exploited by targeted therapy approaches that would be specifically effective in this subset of cancers. We will accelerate our research to tackle the problem of KRAS-mutant lung cancers. We aim to identify potent, tolerable therapies that will target KRAS-mutant lung cancers both with/without intact LKB1. We have used genome-wide genetic screens, metabolic profiling, and kinase inhibitor screens to identify promising therapeutic strategies for LKB1-deficient and -intact KRAS-mutant lung cancers. In particular, we developed a novel screen to identify targets that specifically combine with MEK inhibitors for KRAS-mutant lung cancers, and have already validated one, an MEK and BCL-XL inhibitor combination, that demonstrated impressive activity in genetically-engineered mouse models and xenografts. Since MEK inhibitor-based regimens may not be effective against LKB1 deficient cancers, we developed a novel screen to identify targets whose inhibition is specifically toxic to LKB1-mutant cancers, and validated 2 potential targets, DTYMK and CHEK1, that regulate pyrimidine metabolism and DNA damage response, respectively. We seek to comprehensively develop these potential therapeutic targets in vivo using GEMMs and primary human lung cancer explant xenografts to prepare for clinical implementation of new therapeutic approaches. Further, we will interrogate hundreds of human KRAS-mutant lung cancer specimens to determine if features distinguishing Lkb1-intact and -mutant cancers in the genetically- engineered mouse models are also observed in their human counterparts. We are confident that successful implementation of the aims will yield important mechanistic insights into the signal transduction and metabolic wiring of the various subtypes of KRAS-mutant lung cancers and lead to development of therapeutics that specifically target each subset.