LKB1 is a serine/threonine kinase and tumor suppressor inactivated in 20% of lung cancers. Patients bearing mutant LKB1 have limited response to currently available therapies. Because LKB1 is known to activate a family of 14 kinases, understanding the critical targets of AMPK-related (AMPKR) kinases in lung cancer is critical to develop new therapeutics for LKB1-mutant lung cancers. I identify several novel substrates of the AMPKRs, including multiple small GTPase activating proteins (GAPs) family members, which mediate the tumor suppressive function of LKB1 in mutant KRAS genetically engineered mouse models (GEMMs) and lung cancer cell lines. While all candidate GAPs provided some tumor suppressive function within the lung, the RasGAP protein RAS protein activator like 2 (Rasal2) demonstrated the strongest activation and appears to phenocopy LKB1’s tumor suppressive function in vivo. I identified Rasal2 as a novel salt-inducible kinase (SIK) 1 and 3 substrate that is specifically phosphorylated at two serine sites, serine 56 and serine 89, in an LKB1-dependent manner. Collectively these findings reveal new LKB1-dependent signaling pathways could reveal new potential therapeutic avenues for this patient population. Additionally, I collaborated with Lillian Eichner to identify that HDAC3, a downstream substrate of the SIKs, plays a critical role in KRAS-mutant lung cancer. HDAC3 appears to direct and enhance the transcription effects of NKX2-1, a lung cancer lineage transcription factor, to mediate expression of a set of downstream target genes. Specifically, FGFR1 was identified as a critical new target of HDAC3. Using this, we were able to identify transcriptional cassettes that become hyperactivated in KRAS:LKB1 (KL) double mutant cells that develop resistance to MEK inhibitors such as trametinib, which can be reversed by an HDAC1/3 inhibitor entinostat. The combination of trametinib and entinostat shows therapeutic benefit in the KRAS:LKB1 double mutant GEMM.