title: Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition.
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.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Martijn A J
authors.initials: MA
authors.lastname: Koppens
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Gergana
authors.initials: G
authors.lastname: Bounova
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Paulien
authors.initials: P
authors.lastname: Cornelissen-Steijger
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: de Vries
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of EEMCS, Delft University of Technology, Delft, The Netherlands.|Cancer Genomics Centre Netherlands (CGC.nl), The Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Cancer Genomics Centre Netherlands (CGC.nl), The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D024101:Mitochondrial Proteins; D009154:Mutation; D009940:Organoids; D051762:PAX2 Transcription Factor / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000075924:X-linked Nuclear Protein / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C577920:GSK-2816126; D007211:Indoles; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D011728:Pyridones; D016159:Tumor Suppressor Protein p53; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: GSK126; Tp53; colorectal cancer; organoids; polycomb