Targeted degradation of CDK4/6 by LA-CB1 inhibits EMT and suppresses tumor growth in orthotopic breast cancer

Abstract

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) are central regulators of cell cycle progression and frequently dysregulated in cancers, including breast cancer. While selective CDK4/6 inhibitors like Palbociclib, Ribociclib, and Abemaciclib have shown clinical benefit in hormone receptor-positive (HR+) breast cancer, their efficacy is often limited by resistance mechanisms and dose-limiting toxicities. In this study, we developed LA-CB1, a novel Abemaciclib derivative that induces CDK4/6 degradation through the ubiquitin-proteasome pathway, aiming to achieve sustained inhibition of the CDK4/6-Rb axis. LA-CB1 demonstrated potent anti-proliferative effects in various breast cancer cell lines, with notable efficacy in triple-negative breast cancer (TNBC) and HR + breast cancer models. Molecular docking studies confirmed high-affinity binding of LA-CB1 to the ATP-binding pocket of CDK4/6. Mechanistic studies revealed that LA-CB1 induces G0/G1 cell cycle arrest and promotes apoptosis through the degradation of CDK4/6. Importantly, LA-CB1 also suppressed epithelial-mesenchymal transition (EMT), inhibiting key processes such as cell migration, invasion, and angiogenesis, indicating its ability to disrupt multiple hallmarks of cancer. In an orthotopic breast cancer model, LA-CB1 significantly reduced tumor growth in a dose-dependent manner. These results suggest that LA-CB1 represents a promising therapeutic strategy by targeting CDK4/6 for degradation, addressing limitations associated with current CDK4/6 inhibitors, and providing broad anti-tumor activity in aggressive cancer types like TNBC.