Abstract Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive and lethal malignancies. Development of chemoresistance in PDAC is one of the key contributors for the poor survival outcomes of PDAC patients and the major reason for urgent development of novel pharmacological approaches for effective treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC, but number of possible combinations considering all approved drugs and drug candidates is too large to be explored empirically. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as a game changer but available data indicates their efficacy only in combined therapy settings. In this work, we explored possibility of using drug-sensitivity data together with basal gene expression data on pancreatic cell lines to predict the combinatorial options available for HDACi and developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC. Our results identified sphingolipid signaling pathway with associated downstream effectors as a promising novel target for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.