CDK4/6抑制剂在HR^+和HER2^-晚期乳腺癌中的研究进展

Advances in CDK4/6 inhibitors in HR^+ and HER^2 advanced breast cancer

在乳腺癌的综合治疗中,内分泌治疗是激素受体阳性(hormone receptor-positive,HR+)乳腺癌患者的有效治疗方式之一,但是随着内分泌治疗的长期应用,其有效性受到原发耐药与继发耐药的限制。随着细胞周期蛋白依赖性蛋白激酶(cyclin-dependent protein kinases,CDKs)抑制剂及与其相关的临床试验结果的出现,对于HR+和人表皮生长因子受体2阴性(human epidermal growth factor receptor 2–negative,HER2-)的晚期乳腺癌,CDK4/6抑制剂是逆转内分泌治疗耐药的有效药物,并在无进展生存方面显示出了明显的优势。CDK4/6抑制剂主要通过CDK4/6-cyclin D-视网膜母细胞瘤(retinoblastoma,RB)基因通路来调控细胞周期,且此通路是雌激素受体(estrogen receptor,ER)信号下游的关键靶标,因此阻断CDK4/6的活性,即可恢复细胞周期控制,进而阻断肿瘤细胞增殖。本文主要阐述3种CDK4/6抑制剂(palbociclib、ribociclib和abemaciclib)在HR+和HER2-晚期乳腺癌临床试验中的有效性、安全性以及药代动力学;同时,本文还对CDK4/6抑制剂可能会激发免疫以及可能阻断三阴性乳腺癌细胞的远处转移等相关的最新研究结果进行综述。

In the comprehensive treatment of breast cancer, endocrine therapy has become one of the effective methods for hormone receptor- positive (HR + ) breast cancer. However, the effectiveness of endocrine therapy has been limited by primary resistance and acquired resistance as its long-term application. The clinical trials associated with cyclin-dependent protein kinases (CDKs) inhibitors have proven that the CDK4/6 inhibitors have an effect in reversing the resistance of endocrine therapy for the patients with HR + and human epidermal growth factor receptor 2-negative (HER2 - ) advanced breast cancer, and have significance advantage in progression free survival. CDK4/6 inhibitors can regulate cell cycle mainly by the CDK4/6-cyclin D-retinoblastoma ( RB ) pathway, which is also a key downstream target of estrogen receptor (ER) signal. Therefore, inhibiting the activity of CDK4/6 can restore cell cycle control and further block tumor cell proliferation. This review describes the efficacy, safety and pharmacokinetics of three CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) in clinical trials of HR + and HER2 - advanced breast cancer. This article also reviews the latest research results about CDK4/6 inhibitors stimulating the immune response and blocking the distant metastasis of triple- negative breast cancer cell lines.