Cyclin-dependent kinase 4 and 6 inhibitors in breast cancer treatment

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-04-08 DOI:10.1038/s41388-025-03378-0

Zhengfei Guo, Richard W. Dong, Yusheng Wu, Shengli Dong, Suresh K. Alahari

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Abstract

Breast cancer is the second largest cancer in the world, and it has highest mortality rate in women worldwide. The aberrant activation of the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway plays an important role in uncontrolled breast cancer cell proliferation. Therefore, targeting CDK4/6 to improve overall survival rates has been a strong interest in breast cancer therapeutics. Till date, four CDK4/6 inhibitors have been developed and approved for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer therapies with great success. However, acquired resistance to CDK4/6 inhibitors has emerged and limits their effectiveness in breast cancer. In this review, we systematically discussed the mechanisms of resistance to CDK4/6 inhibitors including the cell cycle-specific and cell cycle-nonspecific mechanisms. Also, we analyzed combination strategies with other signaling inhibitors in clinical and preclinical settings that further expand the clinical application of CDK4/6 inhibitors in future breast cancer therapies.

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周期蛋白依赖性激酶4和6抑制剂在乳腺癌治疗中的应用。

乳腺癌是世界上第二大癌症，也是全世界女性死亡率最高的癌症。细胞周期蛋白依赖性激酶4和6 （CDK4/6）通路的异常激活在不受控制的乳腺癌细胞增殖中起重要作用。因此，靶向CDK4/6以提高总体生存率一直是乳腺癌治疗的强烈兴趣。迄今为止，已有四种CDK4/6抑制剂被开发并批准用于激素受体阳性和人表皮生长因子受体2 （HER2）阴性的转移性乳腺癌治疗，并取得了巨大成功。然而，CDK4/6抑制剂的获得性耐药已经出现，限制了其在乳腺癌中的有效性。在这篇综述中，我们系统地讨论了CDK4/6抑制剂的耐药机制，包括细胞周期特异性和细胞周期非特异性机制。此外，我们在临床和临床前环境中分析了与其他信号抑制剂的联合策略，进一步扩大了CDK4/6抑制剂在未来乳腺癌治疗中的临床应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.