Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib

Purpose Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in pre-clinical studies, but low clinical performance. Here we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor Carfilzomib. Experimental design First, we identified a subpopulation of PDAC derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor Carfilzomib. Then, we selected a transcriptomic signature that predicts Carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy derived pancreatic organoids. Results Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathways and a down regulation of epithelial-mesenchymal transition genes. Interestingly, Carfilzomib sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the novo RNA and protein synthesis compared to the resistant one and, most important, cell death induced by Carfilzomib is dependent of the translational activity. Conclusion We demonstrate the existence of a Carfilzomib sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.