Abstract 1898: CDK2 partners with cyclin E or cyclin A to support distinct roles in cell cycle regulation: Implications for anti-tumor efficacy and potential toxicity of CDK2 inhibitors.

Abstract Cyclin-dependent kinase 2 (CDK2) is the primary regulator of the S phase of the cell cycle, phosphorylating numerous substrates involved in controlling DNA replication origin firing and fork progression. CDK2 initially becomes activated in late G1 via binding to cyclin E (CCNE1/CCNE2), and contributes to phosphorylating RB1 to drive G1/S transition. As S phase progresses, CDK2 activity becomes increasingly dependent on cyclin A (CCNA2) to support the completion of DNA replication and promote activation of CDK1 in the G2 phase. In certain physiological and pathological circumstances, cyclin E overexpression has been shown to hyperactivate CDK2 and promote endoreduplication, inhibit cellular senescence, and/or override cell cycle checkpoints. Many of these features are hallmarks of cancer cells; indeed, copy number amplification of CCNE1 or CCNE2 are observed in subsets of solid tumors (e.g. gastroesophageal, ovarian, and breast cancers), highlighting CDK2 as a promising therapeutic target in these contexts. However, the development of CDK2 inhibitors has been hindered by dose-limiting gastrointestinal (GI) toxicities, and it is unclear whether this is caused by off-target (e.g. CDK1) or on-target inhibition of one or more CDK2-cyclin complexes. Using a combination of genetic and pharmacologic perturbations, we investigated how the different CDK2-cyclin complexes contribute to cell cycle regulation in both cancer and normal GI cell models. Our findings shed light on the underlying mechanisms by which CDK2 inhibition contributes to both anti-cancer efficacy and normal tissue toxicity. Citation Format: Haoran Jing, Neil Umbreit, Rens Janssens, Kimberly Rizzolo, Thao Duong, Huyen Nguyen. CDK2 partners with cyclin E or cyclin A to support distinct roles in cell cycle regulation: Implications for anti-tumor efficacy and potential toxicity of CDK2 inhibitors 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 1898.