Abstract 3099: Selective CDK2 inhibition with ECI830: preclinical characterization, efficacy, and on-target mechanism supported by biomarker and gene signature analysis

Abstract Dysregulation of the cell cycle pathway is a hallmark of many human cancers, enabling uncontrolled cell growth. Cyclin-dependent kinases, exemplified by CDK2, CDK4, and CDK6, play crucial roles in regulating cell cycle progression. While CDK4/6 inhibitors such as ribociclib have transformed the treatment landscape for HR+/HER2− breast cancer, selectively targeting CDK2 has remained challenging due to the high degree of structural similarity to other essential CDK family members, such as CDK1. Genetic and pharmacological studies have shown that CCNE1-amplified cancer models have a dependency on CDK2 and that combined inhibition of CDK2 and CDK4 enhances tumor suppression in HR+/HER2− breast cancer models. Here, we describe the preclinical activity of ECI830, an orally bioavailable and potent adenosine triphosphate-competitive CDK2 inhibitor with high selectivity over other CDK family members. ECI830 demonstrated substantial antiproliferative activity in CCNE1-amplified ovarian (OVCAR3) and lung (H810) cancer cell lines. In an HR+/HER2− breast cancer cell line (MCF7) and several patient-derived xenograft models resistant to standard-of-care treatment, the combination of ECI830 and ribociclib resulted in synergistic activity with deeper pathway suppression, enhanced biomarker modulation, and stronger tumor growth inhibition compared with either agent alone. Mechanistic studies demonstrated that the activity of ECI830, alone or in combination with ribociclib, was on-target. Moreover, ECI830 showed a favorable pharmacokinetics and tolerability profile in preclinical mouse models. Taken together, these promising preclinical data support ECI830 as a selective and potent CDK2 inhibitor for the treatment of HR+/HER2- breast cancer and other CCNE1-dysregulated advanced solid tumors, which is currently being investigated in clinical trials. Citation Format: Ophelia Maertens, Bradley French, Eric Fang, Imad Hanna, Ying Huang, Sajan Joseph, Fallon Lin, Neil Umbreit, Anna Uvarova, Vivek Rauniyar, Samuel Ho. Selective CDK2 inhibition with ECI830: preclinical characterization, efficacy, and on-target mechanism supported by biomarker and gene signature analysis 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 3099.