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

Serresi, M.; Siteur, B.; Hulsman, D.; Company, C.; Schmitt, M.J.; Lieftink, C.; Morris, B.; Cesaroni, M.; Proost, N.; Beijersbergen, R.L.; van Lohuizen, M.; Gargiulo, G.

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., Siteur, B., Hulsman, D., Company, C., Schmitt, M.J., Lieftink, C., Morris, B., Cesaroni, M., Proost, N., Beijersbergen, R.L., 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
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Volume:	215
Number:	12
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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