Mutated K-RAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic K-RAS are still under investigation or awaiting clinical approval. Using a specific K-RAS-dependent gene signature, we implemented a computer-assisted inspection of a drug-gene network to in silico repurpose drugs that work like inhibitors of oncogenic K-RAS. We identified and validated decitabine-a U.S. Food and Drug Administration-approved drug-as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed K-RAS dependency. Mechanistically, decitabine efficacy was linked to K-RAS-driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in K-RAS-dependent tumors cells. These findings also showed that gene signatures related to K-RAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of K-RAS-mutated pancreatic cancer patients. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant K-RAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease.