期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 12, 页码 3115-3135出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20180801
关键词
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资金
- European Union Marie Curie [FP7-PEO PLE-2009-IEF 251938]
- Netherlands Organization for Scientific Research to Cancer Genomics Netherlands
- Dutch Cancer Society [NKI 2013-61093, NKI 2014-7208]
- Fondazione Lorini
- Helmholtz Association
- Max Delbruck Center
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-kappa B 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-kappa B. 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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