Polycomb Deficiency Drives a FOXP2-high Aggressive State Targetable by Epigenetic Inhibitors

The purpose of this research is to understand the role and expand the precision medicine of EZH2 inhibition in lung adenocarcinoma. Our data show that histone methyltransferase EZH2 acts in a context-dependent manner as an oncogene or tumor suppressor in KRAS+/Trp53-null murine lung adenocarcinoma. Moreover, EZH2 deprivation confers sensitivity to histone demethylase and BET inhibitors in 3D culture and in vivo models, representing precision medicine strategies for lung cancers with low canonical EZH2 activity. We found that the embryonic lung transcription factor FOXP2 is de-repressed when EZH2 is inactivated, and FOXP2 promotes stemness and migration, making it a promising therapeutic target. Finally, we identified that high EZH2 correlated with high FOXP2 and poorly differentiated lung cancers, a subgroup that may benefit from combined EZH2 and BET inhibition. RNA-sequencing profiles of KRAS+/Trp53-loss murine lung tumors with Ezh2 wild-type, heterozygous or null from in vitro 2D and 3D cultures and in vivo sorted tumors and fresh total tumors; RNA-sequencing profiles of 2D cells, 3D spheroids and in vivo allgrafts treated with JQ1 or DMSO (vehicle); RNA-sequencing profiles of human cell lines with or without FOXP2-overexpression.