Polycomb Deficiency Drives a FOXP2-high Metastatic 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. Chromatin Immunoprecipitation-sequencing (ChIP-seq) profiles of EZH2 and H3K27me3 binding in KRAS+/Trp53-loss murine lung tumor 3D organoids with Ezh2 wild-type, heterozygous, null or wild-type with EPZ-6438 treatment.