The Polycomb Protein EED Constrains the SCLC Neuroendocrine Phenotype and Drives Lung Cancer Histological Transformation [ATAC-seq]

Lung cancer is comprised of distinct histological subtypes including lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). Although histological subtypes of lung cancer are often mutually exclusive, patients can present with combined LUAD and SCLC histology tumors. Moreover, LUADs can histologically transform to SCLC through lineage plasticity as a mechanism of resistance to targeted therapies, which most often occurs in EGFR-Mutant LUAD with concurrent RB1 and TP53 inactivation after treatment with EGFR inhibitors. The mechanisms that promote LUAD to SCLC histological transformation are poorly understood. Expression of genes associated with PRC2 activity increase during LUAD to SCLC histological transformation, but it is unknown whether PRC2 is a causative driver of histological transformation in lung cancer. To study the role of the PRC2 complex in SCLC tumorigenesis, we used CRISPR-based somatic gene editing to make SCLC genetically-engineered mouse models (GEMMs) deficient for PRC2 through inactivation of EED; PRC2’s core scaffolding subunit. Strikingly, EED inactivation caused complete histological transformation from ASCL1-positive SCLC to LUAD through an intermediate NEUROD1-positive/NCAM-positive cell state. Mechanistically, SCLC to LUAD histological transformation is initiated when PRC2 inactivation de-represses bivalent genes marked by both H3K27me3 and K3K4me3 including RAS, PI3K, and MAPK pathway genes as well as NEUROD1. Lastly, we developed an EGFR-Mutant LUAD GEMM with concurrent RB1 and TP53 inactivation where EGFR inhibition can promote SCLC transformation and a metastatic phenotype; both of which are completely abrogated by EED inactivation. Together, these findings show that the PRC2 complex is required to drive ASCL1-positive neuroendocrine SCLC with its loss promoting the LUAD phenotype nominating PRC2 inhibition as a therapeutic strategy to block SCLC transformation.