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

Camilla Calandrini, Sander R van Hooff, Irene Paassen, Dilara Ayyildiz, Sepide Derakhshan, M Emmy M Dolman, Karin P S Langenberg, Marieke van de Ven, Cecilia de Heus, Nalan Liv, Marcel Kool, Ronald R de Krijger, Godelieve A M Tytgat, Marry M van den Heuvel-Eibrink, Jan J Molenaar, Jarno Drost

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article number109568
Pages (from-to)1-12
JournalCell Reports
Issue number8
Publication statusPublished - 24 Aug 2021


  • Multivalency effects in neuraminidase inhibitor design for influenza virus: This article is dedicated to Professor Horst Kunz on the occasion of his 80th birthday
  • organoids
  • neddylation
  • drug screening
  • MLN4924
  • targeted therapy


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