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

Sep 23, 2026

Uploaded by Ezra

Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell-cycle progression and are frequently dysregulated in breast cancer. This work develops LA-CB1, an Abemaciclib derivative designed to induce ubiquitin-proteasome mediated CDK4/6 degradation to sustain inhibition of the CDK4/6-Rb axis. LA-CB1 shows strong anti-proliferative effects across breast cancer cell lines, including triple-negative and HR+ models, verified by high-affinity docking. Mechanistically, it drives G0/G1 arrest, promotes apoptosis, suppresses EMT, and reduces orthotopic tumor growth in a dose-dependent manner.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Introduction

CDK4/6 in breast cancer and resistance to inhibitors

Rationale for targeted protein degradation and PROTACs

Study Overview and LA-CB1 Design

LA-CB1 as a CDK4/6 degrader through ubiquitin-proteasome pathway

Results and Mechanistic Effects

Cell cycle arrest and apoptosis

EMT suppression and impact on tumor hallmarks

In vivo Evaluation

Orthotopic breast cancer tumor growth effects

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Targeted degradation ofCDK4/6 by LA-CB1 inhibits EMT and suppresses tumor growth in orthotopic breast cancer Jingliang He1,4, Shunfang Liu2,4, Siyi Zhang1,4, Qi Gao1,4, Lan Zhu3, Ningyang Xu3, Zhongke Hu1, Xingyu Zhang1, Shaojie Ma1, Xiujun Wang1, Bin Liu1􀀍 & Wei Liu3􀀍 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 inducesCDK4/6 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 ofCDK4/6 . Mechanistic studies revealed that LA-CB1 induces G0/G1 cell cycle arrest and promotes apoptosis through the degradation ofCDK4/6 . 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. Keywords CDK4/6 degradation, LA-CB1, Cell cycle arrest, Breast cancer, Ubiquitin-proteasome pathway, Epithelial-mesenchymal transition (EMT) Cyclin-dependent kinases 4 and 6 (CDK4/6) play a crucial role in regulating cell cycle progression, specifically in driving the transition from the G1 to S phase by phosphorylating the retinoblastoma (Rb) protein1–3. This phosphorylation event releases E2F transcription factors, which then activate the transcription of genes required for DNA replication and cell cycle continuation4. Dysregulation of the CDK4/6-Rb-E2F pathway is a common feature in various cancers, particularly in breast cancer, where CDK4/6 overactivation leads to uncontrolled cell proliferation and tumor growth5,6. As key drivers of tumor progression, CDK4/6 have become important therapeutic targets7. The development of selective CDK4/6 inhibitors, such as Palbociclib, Ribociclib, and Abemaciclib, has significantly changed the treatment approach for hormone receptor-positive (HR+) breast cancer8–10. These drugs have been shown to extend progression-free survival and improve clinical outcomes by inhibiting the ATP-binding sites of CDK4/6, preventing Rb phosphorylation, and arresting the cell cycle in G1 phase11, 12. However, the success of CDK4/6 inhibitors is often compromised by the emergence of resistance. Mechanisms of resistance include Rb mutations that reduce sensitivity to CDK4/6 inhibition, and compensatory activation 1Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China. 2Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road 1095, Wuhan 430030, China. 3Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. 4Jingliang He, Shunfang Liu, Siyi Zhang and Qi Gao contributed equally to this work. 􀀍 email: [liubin@jou.edu.cn](liubin@jou.edu.cn); [weiliu@mcw.edu](wei

FAQs

What is LA-CB1 and how does it affect CDK4/6?

LA-CB1 is an Abemaciclib derivative that induces CDK4/6 degradation via the ubiquitin-proteasome pathway, aiming for sustained inhibition of the CDK4/6-Rb axis.

How does LA-CB1 inhibit cancer cell growth mechanistically?

LA-CB1 causes G0/G1 cell cycle arrest and promotes apoptosis by degrading CDK4/6. It also suppresses EMT, reducing processes such as migration, invasion, and angiogenesis.

Does LA-CB1 show anti-tumor activity in vivo?

Yes. In an orthotopic breast cancer model, LA-CB1 significantly reduced tumor growth in a dose-dependent manner.

Sep 23, 2026

Uploaded by Ezra