Abstract 5335: A comparative study of CDK2 inhibitors

Abstract CDK2 is a key Cyclin-Dependent Kinase that is responsible for driving cells through the cell cycle. CDK2 is both hyper-activated in a variety of cancers and is a mechanism of resistance to CDK4/6 inhibitors, making it an attractive therapeutic target. Using PF3600 and PF4091 (tagtociclib), we previously showed that upon CDK2 inhibition, cells exhibit a rapid drop in substrate phosphorylation that rebounds within several hours (‘drop-rebound’). We further showed that CDK4/6 activity compensates for inhibition of CDK2 and sustains the proliferative program by maintaining Rb hyper-phosphorylation and E2F transcription, allowing many cell types to continue cycling in drug. With the advent of numerous new CDK2 inhibitors in development and in clinical trials, we sought to compare five CDK2 inhibitors side-by-side. We first show that all five CDK2 inhibitors elicit the drop-rebound in CDK2 activity. Thus, the drop-rebound response to CDK2 inhibition is not drug-specific, but instead reflects how the cell cycle is wired for robustness. Second, we find that GTAI-664 is ten times more potent than other CDK2 inhibitors. This potency advantage paired with improved selectivity may result in greater target coverage at attainable plasma concentrations in preclinical models. In agreement, several xenograft tumor models appear to respond with better tumor growth inhibition when treated with GTAI-664 relative to PF4091. Finally, we test the combinability of CDK2 inhibitors with CDK4/6 inhibitors in vitro and in vivo. We hypothesize that durable cell-cycle arrest requires forcing Rb kinase activity below a specific threshold where the Rb-E2F positive feedback loop is broken. Our results are timely given the increasing interest in CDK2 inhibitors across a variety of cancer types. Citation Format: Lotte P. Watts, Lisa Nguyen, Marissa Baker, John Chionis, Ryan Vong, Advait Nagle, Stephen Dann, Sabrina L. Spencer. A comparative study of CDK2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5335.