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

• Published in: Cell reports (Cambridge) Vol. 36; no. 8; p. 109568
• Main Authors: Calandrini, Camilla, van Hooff, Sander R., Paassen, Irene, Ayyildiz, Dilara, Derakhshan, Sepide, Dolman, M. Emmy M., Langenberg, Karin P.S., van de Ven, Marieke, de Heus, Cecilia, Liv, Nalan, Kool, Marcel, de Krijger, Ronald R., Tytgat, Godelieve A.M., van den Heuvel-Eibrink, Marry M., Molenaar, Jan J., Drost, Jarno
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.08.2021; Elsevier
• Subjects: Animals; Cell Line, Tumor; Cyclopentanes - pharmacology; drug screening; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; malignant rhabdoid tumors; Mice; Mice, Inbred NOD; Mice, SCID; MLN4924; neddylation; organoids; Organoids - metabolism; Pyrimidines - pharmacology; Rhabdoid Tumor - drug therapy; Rhabdoid Tumor - metabolism; targeted therapy; Unfolded Protein Response - drug effects; Xenograft Model Antitumor Assays; malignant rhabdoid tumors; targeted therapy; neddylation; drug screening; MLN4924; organoids
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109568

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. [Display omitted] •Patient-derived organoids can be used to identify tumor-specific drug vulnerabilities•Neddylation inhibitor MLN4924 is cytotoxic for malignant rhabdoid tumors (MRTs)•MLN4924 induces apoptosis in MRTs via activation of the unfolded protein response•Treatment with MLN4924 extends survival in vivo in an MRT PDX mouse model Calandrini et al. identify neddylation as a therapeutic vulnerability for malignant rhabdoid tumors (MRTs), an aggressive and deadly childhood cancer. The neddylation inhibitor MLN4924 specifically induces cell death in MRTs in vitro and extends overall survival in vivo. Neddylation inhibition may, therefore, be a promising therapeutic strategy for MRTs.