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

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 ortho...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 215; no. 12; p. 3115
Main Authors:	Serresi, Michela, Siteur, Bjorn, Hulsman, Danielle, Company, Carlos, Schmitt, Matthias J, Lieftink, Cor, Morris, Ben, Cesaroni, Matteo, Proost, Natalie, Beijersbergen, Roderick L, van Lohuizen, Maarten, Gargiulo, Gaetano
Format:	Journal Article
Language:	English
Published:	United States 03.12.2018
ISSN:	1540-9538, 1540-9538
Online Access:	Get more information
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1540-9538 1540-9538
DOI:	10.1084/jem.20180801