J Cancer 2019; 10(22):5504-5517. doi:10.7150/jca.32628 This issue

Research Paper

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies

Ying Niu1, Junnan Xu1,2, Tao Sun1,✉

1. Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, No. 44 Xiaoheyan Road, Dadong, Shenyang, Liaoning 110042, P.R. China
2. Key Laboratory of Liaoning Breast Cancer Research, Shenyang, Liaoning 110042, P.R. China

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Niu Y, Xu J, Sun T. Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies. J Cancer 2019; 10(22):5504-5517. doi:10.7150/jca.32628. Available from https://www.jcancer.org/v10p5504.htm

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Dysregulated activation of the cyclin-dependent kinases (CDKs) 4/6, leading to uncontrolled cell division, is hallmark of cancers. Further study of the cell cycle will advance the cancer treatment. As powerful and effective drugs, inhibitors of CDK 4/6 have been widely used in clinical practice for several malignancies, particularly against breast cancers driven by the estrogen receptor (ER). Three CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011) and abemaciclib (LY2835219), have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. However, CDK4/6 inhibitors act downstream of many mitogenic signaling pathways, and this has implications for resistance. It is worth to note that the mechanisms of resistance are not very clear. Up to now, a small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitors resistance in breast cancer. On this basis, rational and effective combination therapy is under development. Here we review the current knowledge about the mechanisms and efficacy of CDK4/6 inhibitors, and summarize data on resistance mechanisms to make future combination therapies more accurate and reasonable.

Keywords: CDK 4/6 inhibitors, breast cancer, clinical trials, drug resistance, combination treatment