Abstract PS2-11-28: Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition

Abstract While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit. Recent studies have shown that CDK2 activity is a key mechanism of resistance to CDK4/6i. Adaptation to CDK4 inhibition can arise from the overexpression or amplification of cyclin E1 or E2, leading to increased CDK2 activity that phosphorylates Rb and bypasses CDK4/6i-induced G1 arrest. Additional alterations, such as p53 loss of function, can activate CDK2. It has been proposed that targeting CDK2, in addition to CDK4, can lead to more durable cell cycle arrest in HR+ cancer cells. In this study, we evaluated the preclinical activity of GDC-4198, a next-generation CDK4/2 inhibitor currently being tested in clinical trials, and its potential to address CDK2-driven resistance to CDK4 inhibition. In biochemical kinase activity assays, GDC-4198 has sub-nanomolar potency against CDK4 and is a more potent inhibitor of CDK2 than CDK6/CycD3, unlike approved CDK4/6i. Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor). This observation was most pronounced in cell line models that have developed resistance to CDK4/6i. RNA-seq data collected after 96 hours of treatment confirmed that the effects of GDC-4198 on gene expression are differentiated from CDK4 inhibition alone. In cell viability assays, GDC-4198 induced growth inhibition and sustained cell cycle arrest in a diverse panel of HR+ breast cancer cell lines. Notably, time-course assays demonstrated that parental T-47D cells can reenter the cell cycle within two days after initial arrest under treatment with CDK4/6i, whereas GDC-4198 led to sustained growth inhibition over five days. Across CDK4/6i resistant HR+ cells, engineered via either long-term exposure to palbociclib or CCNE1/2 overexpression, GDC-4198 was substantially more effective at inhibiting growth than approved CDK4/6i or atirmociclib. Notably, the activity of GDC-4198 was comparable to the combination of CDK4 and CDK2 inhibitors. Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib. In xenograft studies of HR+ breast cancer, GDC-4198 demonstrated dose-dependent tumor growth inhibition. Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent with the effects observed in in vitro experiments. Taken together, these preclinical findings demonstrate that GDC-4198 can induce more durable cell cycle arrest than approved CDK4/6i by overcoming CDK2-driven adaptive and intrinsic resistance to CDK4 inhibition. These results suggest that GDC-4198 is a promising investigational agent with the potential to provide benefit to those who have progressed on approved CDK4/6i while prolonging benefit in earlier disease settings. Citation Format: M. Hafner, S. Vartanian, G. Luca, N. Kosaisawe, M. Hwang, E. Lin, L. Wang, J. Oeh, J. Vijay, K. N. Islam, A. Zheng, K. Samy, U. Segal, J. Moffat, D. Zingg, A. Collier, I. Sanidas, J. Xie, S. A. Wander. Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-28.