2. Academic Validation
  3. Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities

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

  • J Exp Med. 2018 Dec 3;215(12):3115-3135. doi: 10.1084/jem.20180801.
Michela Serresi 1,  Bjorn Siteur 2,  Danielle Hulsman 3 4,  Carlos Company 1,  Matthias J Schmitt 1,  Cor Lieftink 5,  Ben Morris 5,  Matteo Cesaroni 6,  Natalie Proost 2,  Roderick L Beijersbergen 5,  Maarten van Lohuizen 7 4,  Gaetano Gargiulo 8
Affiliations

Affiliations

  • 1 Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • 2 Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 3 Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 4 Oncode Institute, Utrecht, Netherlands.
  • 5 Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 6 Fels Institute, Temple University School of Medicine, Philadelphia, PA.
  • 7 Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, Netherlands [email protected].
  • 8 Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany [email protected].
PMID: 30487290 DOI: 10.1084/jem.20180801
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.

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