Spring Laura, Bardia Aditya, Modi Shanu
Center for Targeted Therapies, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Discov Med. 2016 Jan;21(113):65-74.
Dysregulation of the cyclin D-cyclin-dependent kinase (CDK) 4/6-INK4-retinoblastoma (Rb) pathway is an important contributor to endocrine therapy resistance. Recent clinical development of selective inhibitors of CDK4 and CDK6 kinases has led to renewed interest in cell cycle regulators, following experience with relatively non-selective pan-CDK inhibitors that often resulted in limited activity and poor safety profiles in the clinic. The highly selective oral CDK 4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219) are able to inhibit the proliferation of Rb-positive tumor cells and have demonstrated dose-dependent growth inhibition in ER+ breast cancer models. In metastatic breast cancer, all three agents are being explored in combination with endocrine therapy in Phase III studies. Results so far indicated promising efficacy and manageable safety profiles, and led to the FDA approval of palbociclib. Phase II-III studies of these agents, in combination with endocrine therapy, are also underway in early breast cancer in the neoadjuvant and adjuvant settings. Selective CDK 4/6 inhibitors are also being investigated with other targeted agents or chemotherapy in the advanced setting. This article reviews the rationale for targeting cyclin D-CDK 4/6 in hormone receptor-positive (HR+) breast cancer, provides an overview of the available preclinical and clinical data with CDK 4/6 inhibitors in breast cancer to date, and summarizes the main features of ongoing clinical trials of these new agents in breast cancer. Future trials evaluating further combination strategies with CDK 4/6 backbone and translational studies refining predictive biomarkers are needed to help personalize the optimal treatment regimen for individual patients with ER+ breast cancer.
细胞周期蛋白D-细胞周期蛋白依赖性激酶（CDK）4/6-INK4-视网膜母细胞瘤（Rb）通路的失调是内分泌治疗耐药的一个重要原因。在使用相对非选择性的泛CDK抑制剂在临床上常常导致活性有限和安全性不佳之后，CDK4和CDK6激酶选择性抑制剂的近期临床进展引发了对细胞周期调节因子的新兴趣。高选择性口服CDK 4/6抑制剂帕博西尼（PD0332991）、瑞博西尼（LEE011）和阿贝西利（LY2835219）能够抑制Rb阳性肿瘤细胞的增殖，并已在雌激素受体阳性（ER+）乳腺癌模型中显示出剂量依赖性生长抑制作用。在转移性乳腺癌中，所有这三种药物都正在III期研究中与内分泌治疗联合进行探索。迄今为止的结果表明疗效有望且安全性可控，并导致帕博西尼获得美国食品药品监督管理局（FDA）批准。这些药物与内分泌治疗联合的II-III期研究也正在早期乳腺癌的新辅助和辅助治疗中进行。在晚期情况下，选择性CDK 4/6抑制剂也正在与其他靶向药物或化疗联合进行研究。本文综述了在激素受体阳性（HR+）乳腺癌中靶向细胞周期蛋白D-CDK 4/6的理论依据，概述了迄今为止乳腺癌中CDK 4/6抑制剂的临床前和临床数据，并总结了这些新药在乳腺癌中正在进行的临床试验的主要特征。需要未来评估与CDK 4/6主干进一步联合策略的试验以及完善预测生物标志物的转化研究，以帮助为ER+乳腺癌个体患者制定个性化的最佳治疗方案。
