Palbociclib:周期蛋白依赖性激酶4/6抑制剂治疗乳腺癌

Palbociclib:Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer

乳腺癌在我国发病率位居女性恶性肿瘤的第1位。针对雌激素受体(Estrogen receptor,ER)、孕激素受体(Progesterone receptor,PR)的内分泌治疗可延长激素受体(Hormone receptor,HR)阳性乳腺癌患者的生存,是乳腺癌治疗方案的重要组成部分。研究发现HR阳性的乳腺癌生长依赖细胞周期蛋白依赖性激酶(cyclin-dependent kinase,CDK),尤其是CDK4和CDK6,它们可以加快细胞从细胞周期的G1期进入S期的进程,导致细胞的增殖失控。Palbociclib(PD-0332991,lbrance)是一种口服CDK4/6小分子抑制剂。在体外实验和临床试验中,都显示出对于HR阳性乳腺癌生长的抑制,并且与内分泌治疗有协同作用。2015年2月美国FDA批准其联合来曲唑(Letrozole)用于HR阳性和HER2阴性的绝经后晚期(转移性)乳腺癌患者的一线治疗。也有临床试验支持其联合氟维司群应用。本文综述了Palboeiclib的作用机制,体外实验及临床试验。

Breast cancer is the most common cancer in Chinese women. Endocrine therapy can prolong the survival of the patients whose estrogen receptor （ER）and/or progestogen receptor （PR）positive, and has been the mainstay of treatment for hormone receptor-positive （HR＋）breast cancer. The growth of HR-positive breast cancer depends on cyelin-dependent kinase （CDK）, especially CDK 4/6. They can promote progression from the G 1 phase to the S phase of the cell cycle. Palboeiclib（PD-0332991, Ibrance）is an orally small-molecule inhibitor of CDK4 and CDK6. It has high activity in HR-positive breast cancer cell in vitro or in clinical trials, and is synergistic in combination with endocrine therapies. Palbociclib recently received FDA approval for the treatment of HR＋metastatic breast cancer in combination with letrozole, and recent data suggest improved outcome when combined with fulvestrant. In this article, the mechanism of action of CDK 4/6 inhibitors, preclinical studies, ongoing clinical trials in breast cancer are reviewed.