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Tumor Discovery

REVIEW ARTICLE
Cyclin-dependent kinase 4/6 inhibitor resistance

mechanisms and strategies for subsequent
treatment in breast cancer: A comprehensive

review

Yuling Zhang , Bingfeng Chen , Rendong Zhang , Jundong Wu *, and
2
2,3
1
2
2,3
Chunfa Chen *
1 Department of Medical Quality Management, Cancer Hospital of Shantou University Medical
College, Shantou, Guangdong, China
2 The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong,
China
3 The Research Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou
University Medical College, Shantou, Guangdong, China

Abstract
*Corresponding authors:
Jundong Wu Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the
(wujun-dong@163.com) therapeutic landscape for hormone receptor-positive, human epidermal growth
Chunfa Chen
(chenchunfa@stu.edu.cn) factor receptor 2-negative breast cancer, demonstrating significant efficacy
in both early and advanced stages of the disease. Combined with endocrine
Citation: Zhang Y, Chen B,
Zhang R, Wu J, Chen C. Cyclin- therapy, these inhibitors have dramatically improved survival outcomes.
dependent kinase 4/6 inhibitor However, resistance to CDK4/6 inhibitors inevitably develops, posing a significant
resistance mechanisms and challenge in clinical management. Resistance to CDK4/6 inhibitors can develop
strategies for subsequent treatment
in breast cancer: A comprehensive through inherent and acquired fashions, and their mechanisms are explored in
review. Tumor Discov. this comprehensive review. Inherent resistance arises from pre-existing genetic
2025;4(1):27-36. or signaling pathway alterations that diminish cancer cell sensitivity to CDK4/6
doi: 10.36922/td.7107
inhibitors. Acquired resistance, on the other hand, develops over time through
Received: December 8, 2024 mechanisms, such as the activation of alternative signaling pathways or changes
Revised: January 8, 2025 in the tumor microenvironment. The review also examines potential biomarkers
for predicting resistance, especially circulating tumor DNA markers, and discusses
Accepted: January 14, 2025
strategies to overcome resistance. These include combination therapies targeting
Published online: February 5, multiple pathways simultaneously, sequential approaches to delay the onset
2025 of resistance, and the development of next-generation CDK4/6 inhibitors with
Copyright: © 2025 Author(s). improved efficacy and reduced resistance potential. Understanding resistance
This is an Open-Access article mechanisms and developing effective countermeasures are crucial for optimizing
distributed under the terms of the
Creative Commons Attribution patient outcomes and extending the clinical benefits of CDK4/6 inhibitors in
License, permitting distribution, cancer therapy. Leveraging these insights will enable clinicians to personalize
and reproduction in any medium, treatment strategies, ultimately enhancing the long-term effectiveness of CDK4/6
provided the original work is
properly cited. inhibitors in managing breast cancer.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: CDK4/6 inhibitors; Endocrine resistance; Breast cancer; Drug resistance
regard to jurisdictional claims in
published maps and institutional mechanisms; Treatment strategies
affiliations.

Volume 4 Issue 1 (2025) 27 doi: 10.36922/td.7107