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

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 do

SUBMITTER: He J 

PROVIDER: S-EPMC11880390 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature