Lung cancer is the leading cause of cancer-related death in the United States, with a majority, around 85% resulting from non-small cell lung cancer (NSCLC). The overall survival rate for NSCLC is low, due to poor response to targeted therapy and the development of resistance. While immunotherapy is beneficial for about 30% of patients that harbor mutations in the KRAS oncogene, however, does not benefit the vast majority of the patients. In this context, studies showed that the transcriptional co-activator protein, YAP1, a downstream mediator of the Hippo signaling pathway, plays a major role in the stemness, growth, and metastasis of NSCLCs. In the present study, we find that a non-canonical I kinase, TBK1 (Tank-binding Kinase 1) can physically interact and phosphorylate YAP1. Depletion or inhibition of TBK1 significantly elevated the levels of the YAP1 protein, selectively in KRAS mutant lung cancer cells. This occurred through enhanced methylation of YAP1 on arginine residues. TBK1 is known to play an important role in innate immunity but its oncogenic role, especially in the field of lung cancer, is not fully elucidated. Our proposed project will investigate the functional importance of this novel arginine-methylation of YAP1 protein by certain protein arginine-methyl transferases (PRMTs), especially PRMT4/CARM1 and PRMT5. Inhibition of these PRMTs by a pan-PRMT inhibitor significantly downregulated the levels of YAP1 even in the TBK1 depleted condition. These novel findings raise the possibility that inhibiting TBK1 and PRMTs simultaneously might be a viable strategy to combat NSCLCs, and we will examine this in a series of in-depth in vitro and in vivo studies. The Specific Aims which will be covered are: (1) To understand the differential regulation of YAP1 by TBK1 in KRAS versus EGFR mutant lung adenocarcinoma and (2) To study the novel methylation status of YAP1 molecule under TBK1 depletion in KRAS mutant background leading to YAP1 protein stability.