Abstract 3528: EED drives the small cell lung cancer neuroendocrine phenotype in lung cancer histological transformation

Abstract Lung cancer histological transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) can occur as a resistance mechanism to targeted therapies, particularly in EGFR-mutant LUADs with concurrent RB1 and TP53 mutations. SCLC transformation has a poor prognosis and there are no targeted therapies to block SCLC transformation. Increased PRC2 complex expression is correlated with SCLC transformation, but it is unknown whether PRC2 complex is functionally necessary for SCLC transformation. In this study, we investigated the functional role of EED, a scaffolding component of the PRC2 complex, in SCLC tumorigenesis and in LUAD to SCLC transformation utilizing two state-of-the-art CRISPR-based, autochthonous immunocompetent genetically engineered mouse models (GEMMs) with comprehensive genomic, transcriptomic, and epigenomic analyses. In a de novo SCLC GEMM, we show that loss of EED hinders SCLC development and selects for the formation of LUAD through a NEUROD1-positive intermediate cell state. Mechanistically, EED loss de-represses bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes, to promote transformation to LUAD. Consistently, these same signaling pathway genes are bivalently marked and silenced in human SCLC patient-derived xenografts, indicating a conserved PRC2-mediated mechanism to repress LUAD oncogenic signaling to maintain the SCLC neuroendocrine identity. In a novel CRISPR-based EGFR-mutant LUAD GEMM with RB1/TP53 loss, we found EED is necessary for LUAD to SCLC transformation and metastatic progression following EGFR withdrawal. Altogether, these findings identify the PRC2 complex as an epigenetic regulator that maintains the SCLC neuroendocrine identity and highlights EED inhibition as a potential therapeutic approach to prevent SCLC transformation in high-risk LUAD. Citation Format: Yixiang Li, Yasmin N. Laimon, Hyeonseo Cho, Marina Vivero, Gabriel R. De Oliveira, Andrew Delcea, Varunika Savla, Yuting Chen, Yavuz Durmaz, Xintao Qiu, Shweta Kukreja, Rong Li, Talal El Zarif, Wesley S. Lu, McKayla Van Orden, Jacob E Berchuck, Roderick Bronson, Shuqiang Li, Hongbin Ji, Katerina A. Politi, Matthew L. Freedman, Henry Long, Sabina Signoretti, Matthew Gilbert Oser. EED drives the small cell lung cancer neuroendocrine phenotype in lung cancer histological transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3528.