Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities
Authors
- M. Serresi
- B. Siteur
- D. Hulsman
- C. Company
- M.J. Schmitt
- C. Lieftink
- B. Morris
- M. Cesaroni
- N. Proost
- R.L. Beijersbergen
- M. van Lohuizen
- G. Gargiulo
Journal
- Journal of Experimental Medicine
Citation
- J Exp Med 215 (12): 3115
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.