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

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Nicolas A FraunhofferJuan Iovanna

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

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Citations

Oct 26, 2020·Molecular Oncology·Katharina LankesMatthias Wirth
Aug 5, 2021·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Nicolas A FraunhofferNelson Dusetti
Aug 17, 2021·The Journal of Clinical Investigation·Jonathan A KirkArthur M Feldman

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