TY  - JOUR
AU  - Calandrini, Camilla
AU  - van Hooff, Sander R
AU  - Paassen, Irene
AU  - Ayyildiz, Dilara
AU  - Derakhshan, Sepide
AU  - Dolman, M Emmy M
AU  - Langenberg, Karin P S
AU  - van de Ven, Marieke
AU  - de Heus, Cecilia
AU  - Liv, Nalan
AU  - Kool, Marcel
AU  - de Krijger, Ronald R
AU  - Tytgat, Godelieve A M
AU  - van den Heuvel-Eibrink, Marry M
AU  - Molenaar, Jan J
AU  - Drost, Jarno
TI  - Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors.
JO  - Cell reports
VL  - 36
IS  - 8
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - DKFZ-2021-01917
SP  - 109568
PY  - 2021
AB  - 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.
KW  - MLN4924 (Other)
KW  - drug screening (Other)
KW  - malignant rhabdoid tumors (Other)
KW  - neddylation (Other)
KW  - organoids (Other)
KW  - targeted therapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34433038
DO  - DOI:10.1016/j.celrep.2021.109568
UR  - https://inrepo02.dkfz.de/record/170414
ER  -