Print Email Facebook Twitter Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition Title Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition Author Koppens, Martijn A.J. (Netherlands Cancer Institute) Bounova, Gergana (Netherlands Cancer Institute) Cornelissen-Steijger, Paulien (Netherlands Cancer Institute) de Vries, Nienke (Netherlands Cancer Institute) Sansom, Owen J. (Beatson Institute for Cancer Research) Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics; Netherlands Cancer Institute; Cancer Genomics Centre) van Lohuizen, Maarten (Netherlands Cancer Institute; Cancer Genomics Centre) Date 2016-09-13 Abstract EZH2 inhibitors have gained great interest for their use as anti-cancer therapeutics. However, most research has focused on EZH2 mutant cancers and recently adverse effects of EZH2 inactivation have come to light. To determine whether colorectal cancer cells respond to EZH2 inhibition and to explore which factors influence the degree of response, we treated a panel of 20 organoid lines derived from human colon tumors with different concentrations of the EZH2 inhibitor GSK126. The resulting responses were associated with mutation status, gene expression and responses to other drugs. We found that the response to GSK126 treatment greatly varied between organoid lines. Response associated with the mutation status of ATRX and PAX2, and correlated with BIK expression. It also correlated well with response to Nutlin-3a which inhibits MDM2-p53 interaction thereby activating p53 signaling. Sensitivity to EZH2 ablation depended on the presence of wild type p53, as tumor organoids became resistant when p53 was mutated or knocked down. Our exploratory study provides insight into which genetic factors predict sensitivity to EZH2 inhibition. In addition, we show that the response to EZH2 inhibition requires wild type p53. We conclude that a subset of colorectal cancer patients may benefit from EZH2-targeting therapies. Subject GSK126colorectal cancerorganoidspolycombTp53 To reference this document use: http://resolver.tudelft.nl/uuid:8eec49bc-f3c9-40da-a044-9c543c21e3d4 DOI https://doi.org/10.18632/oncotarget.12002 Source OncoTarget, 7 (43), 69816-69828 Part of collection Institutional Repository Document type journal article Rights © 2016 Martijn A.J. Koppens, Gergana Bounova, Paulien Cornelissen-Steijger, Nienke de Vries, Owen J. Sansom, L.F.A. Wessels, Maarten van Lohuizen Files PDF 11717487.pdf 6.91 MB Close viewer /islandora/object/uuid:8eec49bc-f3c9-40da-a044-9c543c21e3d4/datastream/OBJ/view