Abstract PS5-03-13: Combinatory inhibition of Aurora Kinases and EZH2 leads to a synergistic antitumor effect in Triple Negative Breast Cancer

Abstract Triple-negative breast Cancer (TNBC) accounts for around 15-20% of all breast cancers and is associated with poor long-term outcomes. It remains the most challenging subtype to treat because of its aggressive phenotype and limited treatment options. Aurora Kinases are overexpressed in multiple types of solid tumors, including breast cancer. Our preliminary studies discovered that AURKB expression disproportionally increased in African American TNBC patients more than in European American TNBC patients. Aurora kinase inhibitors, such as alisertib (MLN8237), have demonstrated early signals of efficacy with a manageable safety profile for the treatment of patients with locally advanced or metastatic breast cancer (NCT02860000). However, they did not show significant efficacy in TNBC unless combined with chemotherapy. EZH2, a histone methyltransferase and catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has a broad role in cell stemness, and its overexpression promotes the development of many cancers, including TNBC. Multiple independent studies have identified EZH2 as an attractive drug target in TNBC. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have been approved for the treatment of sarcoma and follicular lymphoma in clinical settings. However, EZH2 inhibitors are ineffective at inhibiting TNBC cell growth. We unexpectedly discovered that Aurora Kinases interact with and phosphorylate EZH2, and inhibition of Aurora Kinases upregulates the chromatin silencing marker H3K27me3. Moreover, combined inhibition of EZH2 and Aurora kinases shows a synergistic antitumor effect in TNBC. Phosphorylation of EZH2 by Aurora Kinase could retain EZH2 in the cytosol, leading to a functional shift from a PRC2 complex-dependent activity to a potential non-canonical EZH2 pro-metastatic function. Furthermore, RNA-seq analysis of the TNBC cells treated with Aurora Kinases inhibitors (AKi) Barasertib (AZD1152) and/or EZH2 PROTAC degrader MS177 reveals that AKi inhibits the expression of a panel of genes, which EZH2 degrader also regulates. Combinatory treatment leads to a synergistic effect on this panel of gene expression, which is critical for cell apoptosis, proliferation, and metabolism in TNBC cells. To summarize, we discovered Aurora Kinases have a less-studied, non-canonical oncogenic function, which acts in parallel with the canonical cell division activity to produce more aggressive tumor metastasis phenotypes seen in TNBC. This non-canonical function highly depends on EZH2-mediated cancer cell apoptosis, proliferation, invasion, and metastasis, which differs from the well-known cell division function of Aurora Kinases, regulating chromosomal alignment, segregation, and cytokinesis during mitosis. Citation Format: K. Graciano, C. Liu, B. Ning, H. Guo, J. Xu. Combinatory inhibition of Aurora Kinases and EZH2 leads to a synergistic antitumor effect in Triple Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-03-13.