December 3, 2018
, 3.8 ÂľM TGF-Îą, 1.2 ÂľM IL-6, 0.9 ÂľM TNF-Îą, 0.9 ÂľM IFN-Îł, and 4.0 ÂľM LPS) with and without the addition of 5 ÂľM GSK126. After 24 h, BTZ was added in a dosage range of 0.01 to 300 nM using the TECAN d300e compound printer, including four replicates per dosage condition with randomized well distribution and DMSO normalization. GSK126 treatment was renewed 24 h after the application of BTZ us
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. Š 2018 Serresi et al.
Serresi, M; Siteur, B; Hulsman, D; Company, C; Schmitt, MJ; Lieftink, C; Morris, B; Cesaroni, M; Proost, N; Beijersbergen, RL; van Lohuizen, M; Gargiulo, G;
Journal: J. Exp. Med. Pages: 3115-3135