Zhao Shidi, Zhang Haochen, Yang Na, Yang Jin
Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Transl Cancer Res. 2023 Jun 30;12(6):1617-1634. doi: 10.21037/tcr-22-2807. Epub 2023 Jun 15.
Previous studies have demonstrated that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy are able to effectively improve the prognosis of hormone receptor positive (HR), human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer (ABC). Five CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, dalpiciclib, and trilaciclib have been approved for the treatment of this breast cancer subset at present. The efficacy and safety profile of adding these CDK4/6 inhibitors to endocrine therapies in HR breast cancer has been proved in a number of clinical trials. Besides, extending the application of CDK4/6 inhibitors to HER2 or triple negative breast cancers (TNBCs) has also led to some clinical benefits.
A comprehensive, non-systematic review of the latest literature about CDK4/6 inhibitors resistance in breast cancer was conducted. The examined database was PubMed/MEDLINE, and the last search was run on October 1, 2022.
In this review, the generation of CDK4/6 inhibitors resistance is related to gene alteration, pathway dysregulation, and tumor microenvironment change. With a deeper insight in the mechanisms of CDK4/6 inhibitor resistance, some biomarkers have presented the potential to predict drug resistance and showed prognostic value. Furthermore, in preclinical studies, some modified treatment strategies based on CDK4/6 inhibitors exhibited effectiveness on drug-resistant tumors, suggesting a preventable or reversible drug-resistant status.
This review clarified the current knowledge about mechanisms, the biomarkers to overcome the drug resistance of CDK4/6 inhibitors, and the latest clinical progresses about CDK4/6 inhibitors. Possible approaches to overcome CDK4/6 inhibitors resistance were further discussed. For example, using another CDK4/6 inhibitor, PI3K inhibitor, mTOR inhibitor, or a novel drug.
既往研究表明，细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂联合内分泌治疗能够有效改善激素受体阳性（HR）、人表皮生长因子受体2（HER2）阴性晚期乳腺癌（ABC）的预后。目前已有5种CDK4/6抑制剂，即哌柏西利、瑞博西尼、阿贝西利、达尔西利和曲拉西利获批用于治疗这一乳腺癌亚型。多项临床试验已证实，在HR乳腺癌的内分泌治疗中添加这些CDK4/6抑制剂的疗效和安全性。此外，将CDK4/6抑制剂的应用扩展至HER2或三阴性乳腺癌（TNBC）也带来了一些临床益处。
对有关乳腺癌中CDK4/6抑制剂耐药性的最新文献进行全面的非系统性综述。检索的数据库为PubMed/MEDLINE，最后一次检索于2022年10月1日进行。
在本综述中，CDK4/6抑制剂耐药性的产生与基因改变、信号通路失调和肿瘤微环境变化有关。随着对CDK4/6抑制剂耐药机制的深入了解，一些生物标志物已显示出预测耐药性的潜力并具有预后价值。此外，在临床前研究中，一些基于CDK4/6抑制剂的改良治疗策略对耐药肿瘤显示出有效性，提示耐药状态具有可预防性或可逆性。
本综述阐明了关于CDK4/6抑制剂耐药机制、克服耐药性的生物标志物以及CDK4/6抑制剂最新临床进展的现有知识。进一步讨论了克服CDK4/6抑制剂耐药性的可能方法。例如，使用另一种CDK4/6抑制剂、PI3K抑制剂、mTOR抑制剂或一种新药。
