Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
Abstract
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. 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. 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 CHO...Continue Reading
References
Citations
Related Concepts
Related Feeds
Cancer Genomics (Keystone)
Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.
Carcinoma, Ductal
Ductal carcinoma is a malignant neoplasm involving the ductal systems of any of a number of organs, such as the mammary glands, pancreas, prostate or lacrimal gland. Discover the latest research on ductal carcinoma here.
Apoptosis
Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis