Pancreatic cancer is the third leading cause of cancer deaths in the US, with a dismal 5-year survival rate of 7%. Nearly all pancreatic tumors harbor oncogenic mutations in the KRAS gene, and efforts to target mutant KRAS protein as a therapeutic approach in pancreatic and other cancers have thus far been unsuccessful. An alternative approach to directly targeting KRAS is to identify and target more druggable molecules involved in molecular mechanism and cellular processes downstream of KRAS which are critical for malignant transformation. Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors carry out vital cellular functions and are highly druggable therapeutic targets. Liver X receptors (LXRs) are members of the NR family and are involved in cholesterol transport, glucose metabolism, and modulation of inflammatory responses. Our studies determined the roles of LXRs in regulating tumor cell growth and survival and identified a number of novel LXR ligands (6-phenyl-2-{[3- (trifluoromethyl)phenyl]amino}-3,4-dihydropyrimidin-4-one and 1-(3,5-dimethoxybenzoyl)-4-(2- methylphenyl)piperazine) and their derivatives, which can inhibit pancreatic cancer cells and modulate receptor activity and the expression of key target genes involved in cancer metabolism. These compounds can thus be used in the treatment of pancreatic cancer and other deadly cancers which carry mutations in KRAS and other cancer-related gene.