RT Journal Article
SR Electronic
T1 SUMO pathway inhibition targets an aggressive pancreatic cancer subtype
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1472
OP 1482
DO 10.1136/gutjnl-2018-317856
VO 69
IS 8
A1 Biederstädt, Alexander
A1 Hassan, Zonera
A1 Schneeweis, Christian
A1 Schick, Markus
A1 Schneider, Lara
A1 Muckenhuber, Alexander
A1 Hong, Yingfen
A1 Siegers, Gerrit
A1 Nilsson, Lisa
A1 Wirth, Matthias
A1 Dantes, Zahra
A1 Steiger, Katja
A1 Schunck, Kathrin
A1 Langston, Steve
A1 Lenhof, H-P
A1 Coluccio, Andrea
A1 Orben, Felix
A1 Slawska, Jolanta
A1 Scherger, Anna
A1 Saur, Dieter
A1 Müller, Stefan
A1 Rad, Roland
A1 Weichert, Wilko
A1 Nilsson, Jonas
A1 Reichert, Maximilian
A1 Schneider, Günter
A1 Keller, Ulrich
YR 2020
UL http://gut.bmj.com/content/69/8/1472.abstract
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.