SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Alexander Biederstädt; Zonera Hassan; Christian Schneeweis; Markus Schick; Lara Schneider; Alexander Muckenhuber; Yingfen Hong; Gerrit Siegers; Lisa Nilsson; Matthias Wirth; Zahra Dantes; Katja Steiger; Kathrin Schunck; Steve Langston; H-P Lenhof; Andrea Coluccio; Felix Orben; Jolanta Slawska; Anna Scherger; Dieter Saur; Stefan Müller; Roland Rad; Wilko Weichert; Jonas Nilsson; Maximilian Reichert; Günter Schneider; Ulrich Keller

doi:10.1136/gutjnl-2018-317856

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Alexander Biederstädt, Zonera Hassan, Christian Schneeweis, Markus Schick, Lara Schneider, Alexander Muckenhuber, Yingfen Hong, Gerrit Siegers, Lisa Nilsson, Matthias Wirth, Zahra Dantes, Katja Steiger, Kathrin Schunck, Steve Langston, H-P Lenhof, Andrea Coluccio, Felix Orben, Jolanta Slawska, Anna Scherger, Dieter SaurStefan Müller, Roland Rad, Wilko Weichert, Jonas Nilsson, Maximilian Reichert, Günter Schneider, Ulrich Keller

Research output: Contribution to journal › Article › peer-review

67 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1472-1482
Number of pages	11
Journal	Gut
Volume	69
Issue number	8
DOIs	https://doi.org/10.1136/gutjnl-2018-317856
Publication status	Published - 1 Aug 2020
Externally published	Yes

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Biederstädt, A., Hassan, Z., Schneeweis, C., Schick, M., Schneider, L., Muckenhuber, A., Hong, Y., Siegers, G., Nilsson, L., Wirth, M., Dantes, Z., Steiger, K., Schunck, K., Langston, S., Lenhof, H.-P., Coluccio, A., Orben, F., Slawska, J., Scherger, A., ... Keller, U. (2020). SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. Gut, 69(8), 1472-1482. https://doi.org/10.1136/gutjnl-2018-317856

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title = "SUMO pathway inhibition targets an aggressive pancreatic cancer subtype",

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.",

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author = "Alexander Biederst{\"a}dt and Zonera Hassan and Christian Schneeweis and Markus Schick and Lara Schneider and Alexander Muckenhuber and Yingfen Hong and Gerrit Siegers and Lisa Nilsson and Matthias Wirth and Zahra Dantes and Katja Steiger and Kathrin Schunck and Steve Langston and H-P Lenhof and Andrea Coluccio and Felix Orben and Jolanta Slawska and Anna Scherger and Dieter Saur and Stefan M{\"u}ller and Roland Rad and Wilko Weichert and Jonas Nilsson and Maximilian Reichert and G{\"u}nter Schneider and Ulrich Keller",

year = "2020",

month = aug,

day = "1",

doi = "10.1136/gutjnl-2018-317856",

language = "English",

volume = "69",

pages = "1472--1482",

journal = "Gut",

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publisher = "BMJ Publishing Group",

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}

Biederstädt, A, Hassan, Z, Schneeweis, C, Schick, M, Schneider, L, Muckenhuber, A, Hong, Y, Siegers, G, Nilsson, L, Wirth, M, Dantes, Z, Steiger, K, Schunck, K, Langston, S, Lenhof, H-P, Coluccio, A, Orben, F, Slawska, J, Scherger, A, Saur, D, Müller, S, Rad, R, Weichert, W, Nilsson, J, Reichert, M, Schneider, G & Keller, U 2020, 'SUMO pathway inhibition targets an aggressive pancreatic cancer subtype', Gut, vol. 69, no. 8, pp. 1472-1482. https://doi.org/10.1136/gutjnl-2018-317856

TY - JOUR

T1 - SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

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

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

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.

KW - Aged

KW - Animals

KW - Apoptosis

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Enzyme Inhibitors/pharmacology

KW - Esters/pharmacology

KW - Female

KW - Gene Amplification

KW - Gene Expression

KW - Humans

KW - Male

KW - Mice

KW - Middle Aged

KW - Neoplasm Transplantation

KW - Organoids/metabolism

KW - Pancreatic Neoplasms/drug therapy

KW - Prognosis

KW - Proto-Oncogene Proteins c-myc/genetics

KW - Pyrazoles/pharmacology

KW - Pyrimidines/pharmacology

KW - SUMO-1 Protein/genetics

KW - Small Ubiquitin-Related Modifier Proteins/genetics

KW - Sulfonic Acids

KW - Sumoylation/drug effects

KW - Transcriptome/drug effects

KW - Ubiquitin-Activating Enzymes/antagonists & inhibitors

KW - Ubiquitin-Conjugating Enzymes/genetics

KW - Ubiquitins/genetics

U2 - 10.1136/gutjnl-2018-317856

DO - 10.1136/gutjnl-2018-317856

M3 - Article

C2 - 32001555

SN - 0017-5749

VL - 69

SP - 1472

EP - 1482

JO - Gut

JF - Gut

IS - 8

ER -

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Abstract

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