SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

被引：72

作者：

Biederstadt, Alexander ^{[1
]}

Hassan, Zonera ^{[2
]}

Schneeweis, Christian ^{[2
]}

Schick, Markus ^{[3
]}

Schneider, Lara ^{[4
,5
]}

Muckenhuber, Alexander ^{[6
]}

Hong, Yingfen ^{[1
]}

Siegers, Gerrit ^{[1
]}

Nilsson, Lisa ^{[7
]}

Wirth, Matthias ^{[3
]}

Dantes, Zahra ^{[2
]}

Steiger, Katja ^{[6
,8
,9
]}

Schunck, Kathrin ^{[10
]}

Langston, Steve ^{[11
]}

Lenhof, H-P ^{[4
]}

Coluccio, Andrea ^{[2
,12
]}

Orben, Felix ^{[2
]}

Slawska, Jolanta ^{[1
]}

Scherger, Anna ^{[1
]}

Saur, Dieter ^{[8
,9
,12
]}

Mueller, Stefan ^{[10
]}

Rad, Roland ^{[8
,9
,13
]}

Weichert, Wilko ^{[6
,8
,9
]}

Nilsson, Jonas ^{[7
]}

Reichert, Maximilian ^{[2
,8
,9
]}

Schneider, Gueter ^{[2
,8
,9
]}

Keller, Ulrich ^{[3
,8
,9
]}

机构：

[1] Tech Univ Munich, Med Clin & Policlin 3, Klinikum Rechts Isar, Munich, Germany

[2] Tech Univ Munich, Klinikum Rechts Isar, Med Clin & Polyclin 2, D-81675 Munich, Germany

[3] Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Campus Benjamin Franklin, D-12203 Berlin, Germany

[4] Saarland Univ, Ctr Bioinformat, Saarland Informat Campus, Saarbrucken, Germany

[5] Saarland Univ, Saarbrucken Grad Sch Comp Sci, Saarland Informat Campus, Saarbrucken, Germany

[6] Tech Univ Munich, Inst Pathol, Munich, Germany

[7] Gothenburg Univ, Dept Surg, Sahlgrenska Canc Ctr, Gothenburg, Sweden

[8] German Canc Res Ctr, Heidelberg, Germany

[9] German Canc Consortium DKTK, Heidelberg, Germany

[10] Goethe Univ, Inst Biochem 2, Sch Med, Frankfurt, Germany

[11] Takeda Pharmaceut Int Co, Oncol Drug Discovery Unit, Cambridge, MA USA

[12] Tech Univ Munich, Inst Translat Canc Res & Expt Canc Therapy, Munich, Germany

[13] Tech Univ Munich, Inst Mol Oncol & Funct Genom, Munich, Germany

来源：

GUT | 2020年 / 69卷 / 08期

基金：

芬兰科学院;

关键词：

DUCTAL ADENOCARCINOMA; THERAPEUTIC TARGETS; IN-VITRO; MYC; SUMOYLATION; LANDSCAPE; MODELS; TUMOR; THERAPIES; RESPONSES;

D O I：

10.1136/gutjnl-2018-317856

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：1472 / 1482

页数：11

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