Abstract SY19-03: Mechanisms of sensitivity and resistance to CDK2 inhibitors

Abstract CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. We used several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. In normal mammary cells and estrogen receptor-positive breast cancer cells, CDK2 inhibition causes a rapid loss of substrate phosphorylation that is rapidly restored by a hard-wired cell-cycle buffering mechanism. In this mechanism, CDK4/6 backstops Rb1 hyper-phosphorylation to maintain Cyclin A2 expression, enabling re-activation of CDK2 in the presence of CDK2 inhibitor. By contrast, CCNE1-amplified ovarian cancers do not exhibit this rapid rebound. Our results augment our understanding of CDK plasticity and CDK dependencies, delineate the genetic backgrounds in which this adaptive rebound upon CDK2 inhibition can occur, and suggest contexts in which CDK2 inhibition will be most effective as a cancer therapy. Citation Format: Sabrina L. Spencer. Mechanisms of sensitivity and resistance to CDK2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY19-03.