Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

被引：32

作者：

Calandrini, Camilla ^{[1
,2
]}

van Hooff, Sander R. ^{[1
]}

Paassen, Irene ^{[1
,2
]}

Ayyildiz, Dilara ^{[1
,2
]}

Derakhshan, Sepide ^{[1
,2
]}

Dolman, M. Emmy M. ^{[1
]}

Langenberg, Karin P. S. ^{[1
]}

van de Ven, Marieke ^{[3
]}

de Heus, Cecilia ^{[4
]}

Liv, Nalan ^{[4
]}

Kool, Marcel ^{[1
,5
,6
,7
]}

de Krijger, Ronald R. ^{[1
,8
]}

Tytgat, Godelieve A. M. ^{[1
]}

Van den Heuvel-Eibrink, Marry M. ^{[1
]}

Molenaar, Jan J. ^{[1
]}

Drost, Jarno ^{[1
,2
]}

机构：

[1] Princess Maxima Ctr Pediat Oncol, Heidelberglaan 25, NL-3584 CS Utrecht, Netherlands

[2] Oncode Inst, Heidelberglaan 25, NL-3584 CS Utrecht, Netherlands

[3] NKI, Mouse Clin Canc & Ageing MCCA, Preclin Intervent Unit, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

[4] Univ Med Ctr Utrecht, Ctr Mol Med, Cell Biol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands

[5] Hopp Childrens Canc Ctr KiTZ, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[7] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[8] Univ Med Ctr, Dept Pathol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands

来源：

CELL REPORTS | 2021年 / 36卷 / 08期

基金：

欧洲研究理事会;

关键词：

NEDD8-ACTIVATING ENZYME-INHIBITOR; UP-REGULATION; MLN4924; APOPTOSIS; MUTATIONS; KIDNEY; PEVONEDISTAT; HEPATOCYTES; INDUCTION; REGULATOR;

D O I：

10.1016/j.celrep.2021.109568

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Malignant rhabdoid tumors (MRTs) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is, therefore, dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient response to therapy. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate in vivo efficacy in an MRT PDX mouse model, in which single-agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as a therapeutic strategy in MRT.

引用

页数：16

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