Abstract B142: EO3001: A novel agent for ARID1A mutant cancers

Abstract Background ARID1A mutations are among the most common genetic alterations in cancer, occurring in approximately 65% of ovarian clear cell carcinoma (OCCC) and up to 10% of all solid tumors. These mutations disrupt chromatin remodeling and cellular homeostasis, leading to the accumulation of reactive oxygen species (ROS) and a metabolic shift that renders tumor cells increasingly dependent on oxidative phosphorylation (OXPHOS) for survival. This metabolic vulnerability provides a therapeutic opportunity for selective targeting. EO3001 is a novel synthetic agent that transports extracellular Cu(II) to mitochondria, promoting mitochondrial ROS generation and triggering cancer cell death. Preclinical studies have shown that EO3001 exhibits selective cytotoxicity in ARID1A-deficient CCOC models, highlighting its potential as a precision oncology candidate. Methods To evaluate EO3001’s activity, isogenic CCOC cell lines with and without ARID1A expression were generated using CRISPR-Cas9 gene editing. The compound’s effects were assessed through a series of in vitro and ex vivo assays, measuring cell viability, mitochondrial ROS levels, OXPHOS activity, and invasive potential under various metabolic stress conditions. Notably, EO3001 demonstrated robust anti-tumor activity in ARID1A-deficient cells, with markedly reduced efficacy in hypoxic environments—supporting the mechanism of action linked to OXPHOS dependence. Conclusions and Next Steps These findings suggest that EO3001 holds promise as a targeted therapeutic for ARID1A-mutant cancers, and ongoing work is focused on optimizing its application in clinically relevant settings. A biomarker-driven clinical trial is planed to further evaluate these findings. Citation Format: Jeffrey Bacha, Yuchen Ding, Dennis Brown, Amal M. El-Naggar, David G. Huntsman, Sarath Kanekal, Neil Sankar. EO3001: A novel agent for ARID1A mutant cancers [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 B142.