2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.16: The Polycomb Protein EED Constrains the SCLC Neuroendocrine Phenotype and Drives Lung Cancer Histological Transformation

PP01.16: The Polycomb Protein EED Constrains the SCLC Neuroendocrine Phenotype and Drives Lung Cancer Histological Transformation

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The study explores the role of the Polycomb Repressive Complex 2 (PRC2), specifically the EED protein, in the histological transformation of lung cancer subtypes, focusing on small cell lung cancer (SCLC) and lung adenocarcinoma (LUAD). Lung cancer often presents diverse histological subtypes and can undergo transformation, notably from LUAD to SCLC, as a resistance mechanism to EGFR inhibitors, often involving mutations in EGFR, RB1, and TP53.<br /><br />Using CRISPR-based genetically engineered mouse models (GEMMs), the researchers investigated how PRC2 complex activity through EED affects SCLC tumorigenesis and the EGFR-mutant LUAD transformation to SCLC. The study reveals that inactivating EED promotes transformation from SCLC to LUAD via an intermediate state marked by NEUROD1 and NCAM positivity. This transformation is initiated when PRC2 inactivation de-represses certain genes related to RAS, PI3K, MAPK pathways, and NEUROD1, shifting the tumor phenotype from neuroendocrine SCLC to LUAD.<br /><br />The study further develops a CRISPR-based mouse model of EGFR-mutant LUAD with RB1 and TP53 inactivation, showing that EED deletion inhibits the conversion to SCLC following EGFR inhibitor escape. This demonstrates that EED is crucial for developing ASCL1-positive neuroendocrine SCLC. <br /><br />The findings suggest that PRC2 function is vital for maintaining the SCLC phenotype and its inactivation encourages a shift to LUAD. Consequently, PRC2 inhibition emerges as a potential therapeutic approach to prevent transformation to SCLC in lung cancer, providing insights for possible treatment strategies to combat cancer evolution and drug resistance.

Asset Subtitle

Yixiang Li

Keywords

Polycomb Repressive Complex 2

EED protein

lung cancer

small cell lung cancer

lung adenocarcinoma

EGFR inhibitors

CRISPR

tumor transformation

PRC2 inhibition

cancer resistance