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

Martijn Aj Koppens,Lodewyk Fa Wessels,Gergana Bounova,Owen J Sansom,Paulien Cornelissen-Steijger,Nienke De Vries,Maarten Van Lohuizen

doi:10.18632/oncotarget.12002

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.

Highlights

Elevated levels of the Polycomb Group (PcG) protein EZH2 are found in a wide range of cancer types, and are often correlated with poor prognosis [1, 2]
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
Three Colorectal cancer (CRC) organoid lines had low EZH2 levels, two of which have originally been classified into the stem-like molecular subtype and were unable to be propagated during the initial expansion of the panel

Summary

Introduction

Elevated levels of the Polycomb Group (PcG) protein EZH2 are found in a wide range of cancer types, and are often correlated with poor prognosis [1, 2]. It is crucial to thoroughly investigate the mutational landscape and transcriptional profile that define sensitivity to EZH2 inhibition Such studies require a comprehensive overview of the mutations and gene expression patterns that define tumor types and www.impactjournals.com/oncotarget their subtypes. The recent advances in the intestinal organoid culture system have made it possible to in vitro propagate human CRC tumors without losing the genetic and expressional identity of the original tumor, while the diversity that is found in CRC is largely maintained [18, 19] These advantages over conventional cell lines and mouse models, makes the organoid culture method an excellent tool to assess the drug response patterns across the different CRC subtypes

Methods

Results

Conclusion