Integrated transcriptomic and connectivity mapping analysis predicts receptor tyrosine kinase and proteasome inhibition as therapeutic opportunities in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer with few therapeutic options and poor patient survival. A cost-efficient method which can aid in identifying potential new drugs would be drug repurposing the existing drug compounds. Publicly available transcriptomic data from PDAC and normal pancreas samples were interrogated for a stable disease gene signature. The DE genes were analyzed for functional enrichment and protein-protein interaction networks to predict controlled pathways and hub proteins. The Connectivity Map (CMap) and LINCS perturbation signatures were used to predict compounds that would invert the transcriptional state of PDAC. Candidate drugs were docked against identified target proteins and analyzed for pathway and network level. Integrated computational analyses revealed a strong transcriptomic PDAC signature, and the functional enrichment of biological pathways, including cell cycle regulation, tumor progression and extracellular matrix remodelling. Connectivity mapping revealed an enrichment of both FDA-approved drugs and candidates in trials whose transcriptomic signature exhibited an inverse correlation with the transcriptomic PDAC disease signature. Molecular docking supported potential binding of top candidate compounds to PDAC-associated targets. We discovered that multiple compounds, either already in development/market or at early research/development stage, showed expression signatures that were inversely related to the signature associated with PDAC, and have shown a good predicted binding affinity to some selected protein targets associated with PDAC based on docking predictions.