Oncotarget

Research Papers:

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

Martijn AJ Koppens, Gergana Bounova, Paulien Cornelissen-Steijger, Nienke de Vries, Owen J Sansom, Lodewyk FA Wessels and Maarten van Lohuizen _

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Oncotarget. 2016; 7:69816-69828. https://doi.org/10.18632/oncotarget.12002

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Abstract

Martijn AJ Koppens1,*, Gergana Bounova2,*, Paulien Cornelissen-Steijger1, Nienke de Vries1, Owen J Sansom3, Lodewyk FA Wessels2,4,5, Maarten van Lohuizen1,5

1Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

2Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

3Cancer Research UK Beatson Institute, Glasgow, United Kingdom

4Department of EEMCS, Delft University of Technology, Delft, The Netherlands

5Cancer Genomics Centre Netherlands (CGC.nl), The Netherlands

*These authors contributed equally to this work

Correspondence to:

Maarten van Lohuizen, email: M.V.Lohuizen@NKI.NL

Keywords: GSK126, colorectal cancer, organoids, polycomb, Tp53

Received: June 06, 2016     Accepted: September 04, 2016     Published: September 13, 2016

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.


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