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

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Item Type:Article
Title:Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities
Creators Name:Serresi, M. and Siteur, B. and Hulsman, D. and Company, C. and Schmitt, M.J. and Lieftink, C. and Morris, B. and Cesaroni, M. and Proost, N. and Beijersbergen, R.L. and van Lohuizen, M. and Gargiulo, G.
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.
Keywords:A549 Cells, Bortezomib, Cell Proliferation, Enhancer of Zeste Homolog 2 Protein, Inbred BALB C Mice, Indoles, Inflammation, Lung Neoplasms, Non-Small-Cell Lung Carcinoma, Nude Mice, Proto-Oncogene Proteins p21(ras), Pyridones, Sulfonamides, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:3115
Date:3 December 2018
Official Publication:https://doi.org/10.1084/jem.20180801
PubMed:View item in PubMed

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