Abstract LB-204: Neoadjuvant Ezh2 inhibition amplifies an inflammatory program and sensitizes Kras-driven NSCLC to anti-NF-κB inhibition

Kras mutant non-small cell lung cancer (NSCLC) is a leading cause of death but has limited therapeutic options. We investigated the impact of Polycomb repressive complex 2 (PRC2) inhibitors as single agent or as neoadjuvant treatment for subsequent anti-inflammatory therapy. Using orthotopic grafts, we show that Kras cells highly expressing the PRC2 enzymatic component Ezh2 display sensitivity to its inhibition. Ezh2 inhibition leads to transcriptional amplification of an inflammatory program involving NF-kB. Pharmacological inhibition of Ezh2 rerouted Kras tumor progression towards exploiting PRC2/NF-kB target genes as inferred by in vivo RNAi screen but also enhanced the response of Kras NSCLC to a combination of Nimesulide and Bortezomib. These data suggest that low PRC2 levels in Kras-driven NSCLC promote an epigenetic switch, providing a rationale for exploring a novel therapeutic option in which Ezh2 simultaneously acts as biomarker for therapeutic decision and as a neoadjuvant target for therapy. Citation Format: Michela Serresi, Bjorn Siteur, Matteo Cesaroni, Natalie Proost, Danielle Hulsman, Maarten van Lohuizen, Gaetano Gargiulo. Neoadjuvant Ezh2 inhibition amplifies an inflammatory program and sensitizes Kras-driven NSCLC to anti-NF-κB inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-204.