Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal
cancer with a survival rate less than 5%. 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 preclinical 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 pathway
and a downregulation 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 phe�notype showed a high level of the de novo RNA and protein
synthesis compared with the resistant one and, most important,
cell death induced by carfilzomib is dependent of the transla�tional activity.
Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic
phenotype that could explain the biological reason for this
responsiveness