Guo Zhengfei, Dong Richard W, Wu Yusheng, Dong Shengli, Alahari Suresh K
TYK Medicines, Inc., Huzhou, Zhejiang, 313100, China.
Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA.
Oncogene. 2025 May;44(17):1135-1152. doi: 10.1038/s41388-025-03378-0. Epub 2025 Apr 8.
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.
乳腺癌是全球第二大癌症，在全球女性中死亡率最高。细胞周期蛋白依赖性激酶4和6（CDK4/6）通路的异常激活在乳腺癌细胞的失控增殖中起重要作用。因此，靶向CDK4/6以提高总体生存率一直是乳腺癌治疗领域的研究热点。迄今为止，已有四种CDK4/6抑制剂被研发并获批用于激素受体阳性和人表皮生长因子受体2（HER2）阴性转移性乳腺癌的治疗，且取得了巨大成功。然而，对CDK4/6抑制剂的获得性耐药已经出现，并限制了它们在乳腺癌治疗中的有效性。在这篇综述中，我们系统地讨论了对CDK4/6抑制剂耐药的机制，包括细胞周期特异性和细胞周期非特异性机制。此外，我们还分析了在临床和临床前环境中与其他信号抑制剂联合使用的策略，这些策略将进一步扩大CDK4/6抑制剂在未来乳腺癌治疗中的临床应用。
