GDC-4198——一种新一代CDK4/2抑制剂，可诱导持久的细胞周期阻滞，并与giredestrant联用显示出协同获益

While CDK4/6 inhibitors (CDK4/6i) have improved the treatment of hormone receptor-positive (HR+) breast cancer (BC), resistance remains a major clinical challenge. Resistance to CDK4 inhibition can be driven by higher CDK2 activity, due to overexpression of cyclin E1/E2 or p53 loss of function, and other mechanisms. As such, targeting both CDK4 and CDK2 is hypothesized to achieve more durable cell cycle arrest. This study evaluated the preclinical activity of GDC-4198, a novel CDK4/2 inhibitor currently in early clinical trials, and its potential to overcome CDK2-driven resistance to CDK4 inhibition as a single-agent and in combination with giredestrant, a novel selective estrogen receptor (ER) degrader and full ER antagonist. GDC-4198 has sub-nanomolar potency against CDK4/CycD1 and is a more potent inhibitor of CDK2/CycE or CDK2/CycA than CDK6/CycD3, unlike approved CDK4/6i. Western blots and immunofluorescence data demonstrated that GDC-4198 can directly decrease levels of pNCL, a direct marker of CDK2 activity. Cells engineered with a CDK2-activity reporter further confirmed the difference in inhibition profile of GDC-4198 compared to first generation CDK4/6i. In cell viability assays, we observed that GDC-4198 can maintain more durable growth arrest than CDK4/6 or CDK4-targeted inhibitors. Moreover, the introduction of TP53 knock-out had limited effects on GDC-4198 activity, and its potency was not changed by the overexpression of CCNE1/2, in contrast to other CDK inhibitors. Notably, across these different assays, the single-agent activity of GDC-4198 was comparable to the combination of CDK4- and CDK2-targeting agents. 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 cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced anti-proliferation activity of GDC-4198 compared to CDK4/6i. When combined with giredestrant, GDC-4198 showed strong combination benefits across a range of HR+ BC cell lines. In xenograft HR+ BC models, GDC-4198 demonstrated dose-dependent tumor growth inhibition as a single agent and further improved antitumor activity in combination with giredestrant. Pharmacokinetic and pharmacodynamic analyses indicated pRb modulation in tumor samples correlated with drug exposure. Taken together, these preclinical findings demonstrate that GDC-4198 induces more durable cell cycle arrest than first generation CDK4/6i and CDK4-targeting agents by overcoming CDK2-driven adaptive and intrinsic resistance to CDK4 inhibition. These results suggest that GDC-4198 is a promising next generation CDK4/2 inhibitor with the potential to prolong clinical benefit by delaying adaptation in earlier disease settings, as well as to provide benefit to patients who have progressed on approved CDK4/6i.