Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition

Koppens, M. A.J., Bounova, G., Cornelissen-Steijger, P., de Vries, N., Sansom, O. J. , Wessels, L. F.A. and van Lohuizen, M. (2016) Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition. Oncotarget, 7(43), pp. 69816-69828. (doi:10.18632/oncotarget.12002) (PMID:27634879) (PMCID:PMC5342517)

[img]
Preview
Text
140002.pdf - Published Version
Available under License Creative Commons Attribution.

7MB

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: Koppens, M. A.J., Bounova, G., Cornelissen-Steijger, P., de Vries, N., Sansom, O. J., Wessels, L. F.A., and van Lohuizen, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
ISSN (Online):1949-2553
Published Online:13 September 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Oncotarget 7(43):69816-69828
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record