PT  - JOURNAL ARTICLE
AU  - Biederstädt, Alexander
AU  - Hassan, Zonera
AU  - Schneeweis, Christian
AU  - Schick, Markus
AU  - Schneider, Lara
AU  - Muckenhuber, Alexander
AU  - Hong, Yingfen
AU  - Siegers, Gerrit
AU  - Nilsson, Lisa
AU  - Wirth, Matthias
AU  - Dantes, Zahra
AU  - Steiger, Katja
AU  - Schunck, Kathrin
AU  - Langston, Steve
AU  - Lenhof, H-P
AU  - Coluccio, Andrea
AU  - Orben, Felix
AU  - Slawska, Jolanta
AU  - Scherger, Anna
AU  - Saur, Dieter
AU  - Müller, Stefan
AU  - Rad, Roland
AU  - Weichert, Wilko
AU  - Nilsson, Jonas
AU  - Reichert, Maximilian
AU  - Schneider, Günter
AU  - Keller, Ulrich
TI  - SUMO pathway inhibition targets an aggressive pancreatic cancer subtype
AID  - 10.1136/gutjnl-2018-317856
DP  - 2020 Aug 01
TA  - Gut
PG  - 1472--1482
VI  - 69
IP  - 8
4099  - http://gut.bmj.com/content/69/8/1472.short
4100  - http://gut.bmj.com/content/69/8/1472.full
SO  - Gut2020 Aug 01; 69
AB  - 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.