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J Exp Med. 2018 Dec 3;215(12):3115-3135. doi: 10.1084/jem.20180801. Epub 2018 Nov 28.

Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities.

Author information

1
Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
2
Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands.
3
Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, Netherlands.
4
Oncode Institute, Utrecht, Netherlands.
5
Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands.
6
Fels Institute, Temple University School of Medicine, Philadelphia, PA.
7
Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, Netherlands m.v.lohuizen@nki.nl.
8
Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany gaetano.gargiulo@mdc-berlin.de.

Abstract

Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs.

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