Targeted degradation of CDK4/6 by LA-CB1 inhibits EMT and suppresses tumor growth in orthotopic breast cancer. Sci Rep 2025 Mar 04;15(1):7605
Date
03/05/2025Pubmed ID
40038413Pubmed Central ID
PMC11880390DOI
10.1038/s41598-025-92494-8Scopus ID
2-s2.0-86000087831 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
He J, Liu S, Zhang S, Gao Q, Zhu L, Xu N, Hu Z, Zhang X, Ma S, Wang X, Liu B, Liu WAuthor
Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AminopyridinesAnimals
Antineoplastic Agents
Apoptosis
Benzimidazoles
Breast Neoplasms
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Epithelial-Mesenchymal Transition
Female
Humans
Mice
Mice, Nude
Molecular Docking Simulation
Protein Kinase Inhibitors
Proteolysis
Triple Negative Breast Neoplasms
Xenograft Model Antitumor Assays
