| First Author | Serresi M | Year | 2018 |
| Journal | J Exp Med | Volume | 215 |
| Issue | 12 | Pages | 3115-3135 |
| PubMed ID | 30487290 | Mgi Jnum | J:268971 |
| Mgi Id | MGI:6272886 | Doi | 10.1084/jem.20180801 |
| Citation | Serresi M, et al. (2018) Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities. J Exp Med 215(12):3115-3135 |
| abstractText | 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-kappaB 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-kappaB. 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. |
