Lung cancer is the leading cause of cancer-related deaths worldwide. In lung adenocarcinoma, LKB1 (STK11) is among the most frequently inactivated genes, and functional studies in vivo have revealed that LKB1 is a critical suppressor of lung tumor growth. LKB1 encodes a serine-threonine kinase that activates the AMP-activated protein kinase (AMPK) via phosphorylation during energetic stress. AMPK belongs to a family of 14 AMPK-related kinases (AMPKRs), each of which is activated by LKB1-mediated phosphorylation. In addition to defining a critical role for AMPK in supporting lung tumor growth, we identified the salt-inducible kinases (SIKs) as key effectors in LKB1-mediated tumor suppression. The substrates of these AMPKRs that are most critical for either the support or constraint lung tumor growth remain to be identified. Thus, our understanding of the identity and functional significance of LKB1-governed processes in lung cancer remains incomplete. To ascertain the function of AMPKR substrates, we are performing a CRISPR/Cas9 screen in mouse models of oncogenic KRAS-driven lung tumorigenesis. Leveraging next generation-sequencing-based identification of tumor genotype and measurement of individual tumor sizes, we will assess the impact of genetic deficiencies in AMPKR substrates on lung tumor initiation and growth. Among the candidate genes in this screen are those encoding established AMPKR substrates in addition to predicted AMPKR substrates that undergo LKB1-dependent changes in phosphorylation state. These studies will not only yield further insight into the molecular mechanisms by which LKB1 constrains lung tumor growth but also potentially highlight AMPKR-regulated processes that are most critical for supporting lung tumorigenesis.