前情提要
2017年6月3日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表纽约哥伦比亚大学的肿瘤生物学述评：乳腺癌细胞周期疗法的时代到来。
纽约哥伦比亚大学：该校知名校友包括大小罗斯福、艾森豪威尔、奥巴马、格林斯潘、巴菲特、IBM创始人、沃尔玛老板、摩根士丹利CEO、核潜艇之父、调频广播发明者、马寅初、陶行知、胡适、宋子文、金岳霖、冯友兰、李政道、李开复、王力宏太太、李云迪女友、京东老板娘……
保持随时扩散能力是癌症的特征。细胞分裂的正常过程按照细胞周期发生，通过与细胞周期蛋白依赖型激酶（CDK）相关的特定细胞周期蛋白，这一系列高度受控的步骤在分子水平有条不紊地进行。
细胞周期蛋白D和CDK4/6，通过对视网膜母细胞瘤蛋白（一种抑制G1至S期进展的肿瘤抑制因子）进行磷酸化和灭活，在细胞周期进程中发挥关键作用。第一代CDK抑制剂对多种CDK表现广泛活性，这可能解释了其相当大的毒性和有限的效果。
辉瑞的帕泊昔布（帕泊昔克利布，PD-0332991，Ibrance）、诺华的利泊昔布（利泊昔克利布，LEE011，Kisqali）、礼来的阿本昔布（阿本昔克利布，LY2835219）代表了一类新型高度特异性ATP竞争型CDK4/6抑制剂，其在视网膜母细胞瘤阳性肿瘤模型中，可逆性诱导细胞周期止于G1期。根据无进展生存的改善（PALOMA-2、MONALEESA-2），帕泊昔布、利泊昔布已被批准联合内分泌疗法（来曲唑）用于一线治疗激素受体阳性晚期乳腺癌。
通常，CDK4/6抑制剂单药即有细胞抑制作用，但是由于表现出良好的耐受性，促使其被用于联合疗法。联合磷脂酰肌醇3-激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂用于乳腺癌、联合RAS/RAF/MAPK（丝裂原活化蛋白激酶）通路抑制剂用于RAS突变癌，是目前正在评估的、特别有希望的联合疗法。
虽然临床前研究紧锣密鼓地开展，但是预测这些药物有效性和耐药性的生物标志绝大部分仍未明确。因此，CDK4/6抑制剂已经成为最有希望的细胞周期治疗药物，目前正在加紧努力，扩大对该典范的探索。
J Clin Oncol. 2017 Jun 3. [Epub ahead of print]
Biology of Neoplasia: Cell-Cycle Therapeutics Come of Age.
Ingham M, Schwartz GK.
Columbia University School of Medicine, New York, NY.
The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naive hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm.
PMID: 28580868
DOI: 10.1200/JCO.2016.69.0032
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