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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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