Abstract C028: Targeted Degradation of EZH2 Disrupts PRC2 Integrity and Suppresses Breast and Ovarian Tumor Progression

Abstract Background EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), is a key oncogenic driver in breast and ovarian cancers through its role in epigenetic silencing of tumor suppressor genes. While catalytic EZH2 inhibitors such as tazemetostat have shown clinical benefit in hematologic malignancies, their activity in solid tumors remains modest, potentially due to retained PRC2 complex integrity. PROTAC-mediated degradation offers a mechanistically distinct approach capable of dismantling oncogenic multiprotein complexes and achieving more durable target suppression. Methods We systematically evaluated the antitumor activity of EZH2-directed PROTACs in breast and epithelial ovarian cancer models, benchmarking their effects against tazemetostat. Functional assays included viability, clonogenicity, invasion, and adhesion. Western blotting and flow cytometry assessed protein stability, cell cycle distribution, and apoptosis. Transcriptomic effects of degradation versus inhibition were profiled by RNA-seq. Results MS8815, a selective EZH2 degrader, potently impaired cell viability across BRCA and EOC lines, outperforming enzymatic inhibition. EZH2 degradation led to concomitant loss of SUZ12 and EED, indicating collapse of PRC2 integrity. MS8815 impaired 3D invasion, reduced cell adhesion, and suppressed colony outgrowth. Mechanistically, it induced G2/M arrest and apoptosis, associated with downregulation of cyclin B1 and Wee1, and upregulation of cleaved PARP and caspase-3. Transcriptomic analysis revealed broader gene expression reprogramming with PROTAC treatment, including epigenetic and cell cycle regulators not responsive to inhibition alone. Conclusion PROTAC-mediated degradation of EZH2 elicits superior antitumor activity in solid tumor models compared to enzymatic inhibition, driven by comprehensive disruption of PRC2 architecture and sustained epigenetic reprogramming. These findings provide a mechanistic rationale for advancing EZH2 degraders as next-generation epigenetic therapies in PRC2-dependent cancers. Citation Format: Adrian Sanvicente, Cristina Diaz-Tejeiro, Lucia Paniagua-Herranz, Pablo Rodriguez-Olmedo, Cristina Nieto-Jimenez, Alberto Ocaña. Targeted Degradation of EZH2 Disrupts PRC2 Integrity and Suppresses Breast and Ovarian Tumor Progression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C028.