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SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

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Item Type:Article
Title:SUMO pathway inhibition targets an aggressive pancreatic cancer subtype
Creators Name:Biederstädt, A. and Hassan, Z. and Schneeweis, C. and Schick, M. and Schneider, L. and Muckenhuber, A. and Hong, Y. and Siegers, G. and Nilsson, L. and Wirth, M. and Dantes, Z. and Steiger, K. and Schunck, K. and Langston, S. and Lenhof, H.P. and Coluccio, A. and Orben, F. and Slawska, J. and Scherger, A. and Saur, D. and Müller, S. and Rad, R. and Weichert, W. and Nilsson, J. and Reichert, M. and Schneider, G. and Keller, U.
Abstract:OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Keywords:Apoptosis, Cell Proliferation, Enzyme Inhibitors, Gene Amplification, Gene Expression, Neoplasm Transplantation, Organoids, Pancreatic Ductal Carcinoma, Pancreatic Neoplasms, Prognosis, Proto-Oncogene Proteins c-myc, SUMO-1 Protein, Small Ubiquitin-Related Modifier Proteins, Sumoylation, Transcriptome, Tumor Cell Line, Ubiquitin-Activating Enzymes, Ubiquitin-Conjugating Enzymes, Ubiquitins, Animals, Mice
Publisher:BMJ Publishing Group
Page Range:1472-1482
Date:August 2020
Official Publication:https://doi.org/10.1136/gutjnl-2018-317856
PubMed:View item in PubMed

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