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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.


DOI

doi:10.1084/jem.20180801