靶向抑制CDK4/6的肿瘤治疗基础研究与临床应用进展

doi:10.12092/j.issn.1009-2501.2019.09.016

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (9): 1065-1069.doi: 10.12092/j.issn.1009-2501.2019.09.016

靶向抑制CDK4/6的肿瘤治疗基础研究与临床应用进展

吴丽梅，程丽艳，郑晓亮，王孝举

浙江省医学科学院分子医学中心，杭州 310013，浙江

收稿日期:2019-04-02 修回日期:2019-04-28 出版日期:2019-09-26 发布日期:2019-09-26
通讯作者: 王孝举，男，博士，研究员，硕士生导师，研究方向：抗肿瘤药物研究。 Tel: 0571-88215563 E-mail: wangxj@zjams.com.cn
作者简介:吴丽梅，女，硕士研究生，研究方向：抗肿瘤药物研究。 Tel: 13685752064 E-mail：1044267802@qq.com
基金资助:
国家自然科学基金（81773626）；浙江省自然科学基金（LQY19H160001）

Progress in basic research and clinical application of CDK4/6 inhibitor in tumor therapy

WU Limei, CHENG Liyan, ZHENG Xiaoliang, WANG Xiaoju

Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou 310013, Zhejiang,China

Received:2019-04-02 Revised:2019-04-28 Online:2019-09-26 Published:2019-09-26

摘要/Abstract

摘要：

周期蛋白依赖性激酶4/6(cyclin-dependent kinase 4/6，CDK4/6) 是一类丝氨酸/苏氨酸激酶，通过与细胞周期蛋白D（cyclin D）结合，调节视网膜母细胞瘤蛋白(Rb)的磷酸化状态，Rb磷酸化后与E2F转录因子分离，释放的E2F可以自由激活一系列基因表达，参与DNA复制和细胞分裂，从而介导细胞G1/S期转换，影响细胞周期的进程。近年研究发现CDK4/6在多种肿瘤发生和发展过程中起着核心作用，已成为临床多种肿瘤治疗的重要分子靶点。本文将对CDK4/6与肿瘤的关系以及CDK4/6抑制剂临床应用的最新研究进展做一综述。

关键词: 细胞周期依赖性激酶4/6, 细胞周期蛋白D, CDK4/6抑制剂, 肿瘤靶向治疗

Abstract:

Cyclin-dependent kinase 4/6 (CDK4/6) is a serine/threonine kinase that regulates the phosphorylation state of retinoblastoma protein (Rb) by binding to cyclin D.Phosphorylated Rb releases E2F that freely activates a series of gene expression to participate in DNA replication and cell division, which mediates cell G1/S phase transition, affects the progression of the cell cycle. Recent studies have found that CDK4/6 plays a central role in tumorigenesis and development, and has become an important molecular target for clinical treatment of various tumors. This article will review the latest research progress in the relationship between CDK4/6 and tumors and the clinical application of CDK4/6 inhibitors.

Key words: cyclin-dependent kinase 4/6, cyclin D, CDK4/6 inhibitors, tumor targeted therapy

中图分类号:

吴丽梅，程丽艳，郑晓亮，王孝举. 靶向抑制CDK4/6的肿瘤治疗基础研究与临床应用进展[J]. 中国临床药理学与治疗学, 2019, 24(9): 1065-1069.

WU Limei, CHENG Liyan, ZHENG Xiaoliang, WANG Xiaoju. Progress in basic research and clinical application of CDK4/6 inhibitor in tumor therapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(9): 1065-1069.

参考文献

［1］Paternot S, Bockstaele L, Bisteau X, et al. Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase［J］. Cell Cycle, 2010, 9(4): 689-699.
［2］Cassier P, Trédan O, Seigne C, et al. Identifying actionable targets in advanced cancer patients: preliminary results from the profiler program［J］. J Clinic Oncolo, 2014, 32(15): 2621.
［3］Santarius T, Shipley J, Brewer D, et al.A census of amplified and overexpressed human cancer genes［J］.Nat Rev Cancer，2010，10(1):59-64.
［4］Bergsagel PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma［J］. Blood, 2005, 106(1): 296-303.
［5］Koboldt Dc FR, Mclellan Md, Schmidt H, et al.Comprehensive molecular portraits of human breast tumours［J］. Nature, 2012, 490(7418): 61-70.
［6］Lundberg A, Lindstrom LS, Li J, et al.The long-term prognostic and predictive capacity of cyclin D1 gene amplification in 2305 breast tumours［J］. Breast Cancer Res, 2019, 21(1): 34.
［7］Matsuo H, Yoshida K, Fukumura K, et al.Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia［J］. Blood Adv, 2018, 2(21): 2879-2889.
［8］Xiong Y, Li T, Assani G, et al. Ribociclib, a selective cyclin D kinase 4/6 inhibitor, inhibits proliferation and induces apoptosis of human cervical cancer in vitro and in vivo［J］. Biomed Pharmacother, 2019, 112: 108602.
［9］Zhou R, Shi C, Tao W, et al.Analysis of mucosal melanoma whole-genome landscapes reveals clinically relevant genomic aberrations［J］. Clin Cancer Res, 2019，25(12):3548-3560.
［10］Ouyang Z, Wang S, Zeng M, et al.Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target［J］. Cell Commun Signal, 2019, 17(1): 17.
［11］Roskoski R Jr. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs［J］. Pharmacol Res, 2016, 107: 249-275.
［12］Wudu M, Ren H, Hui L, et al. DRAM2 acts as an oncogene in non-small cell lung cancer and suppresses the expression of p53［J］. J Exp Clin Cancer Res，2019, 38(1): 72.
［13］Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib［J］. Breast Cancer Res Treat, 2017, 166(1): 41-54.
［14］Chou A, Froio D, Nagrial AM, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer［J］. Gut，2018, 67(12): 2142-2155.
［15］Tamura K, Mukai H, Naito Y, et al. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients［J］. Cancer Sci, 2016, 107(6): 755-763.
［16］Saab R, Bills JL, Miceli AP, et al. Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells［J］.Mol Cancer Ther, 2006, 5(5): 1299-1308.
［17］Perez M, Munoz-Galvan S, Jimenez-Garcia MP, et al. Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA［J］. Oncotarget, 2015, 6(38): 40557-40574.
［18］Nie H, Zhou X, Shuzhang D, et al. Palbociclib overcomes afatinib resistance in non-small cell lung cancer［J］. Biomed Pharmacother, 2019, 109: 1750-1757.
［19］Chen L, Pan J.Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells［J］. Br J Pharmacol, 2017, 174(15): 2427-2443.
［20］陈本川. 治疗晚期乳腺癌新药--瑞博西尼(ribociclib)［J］. 医药导报, 2017,36(8):945-951.
［21］Curigliano G, Criscitiello C, Esposito A, et al. Pharmacokinetic drug evaluation of ribociclib for the treatment of metastatic, hormone-positive breast cancer［J］. Expert Opin Drug Metab Toxicol, 2017, 13(5): 575-581.
［22］Kim S, Tiedt R, Loo A, et al. The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models［J］. Oncotarget, 2018, 9(81): 35226-35240.
［23］Tai TS, Lin PM, Wu CF, et al. CDK4/6 inhibitor LEE011 is a potential radiation-sensitizer in head and neck squamous cell carcinoma: an in vitro study［J］. Anticancer Res, 2019, 39(2): 713-720.
［24］Dowless M, Lowery CD, Shackleford T, et al. Abemaciclib is active in preclinical models of ewing sarcoma via multipronged regulation of cell cycle, dna methylation, and interferon pathway signaling［J］. Clin Cancer Res, 2018, 24(23): 6028-6039.
［25］Yadav V, Burke TF, Huber L, et al.The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation［J］.Mol Cancer Ther, 2014, 13(10): 2253-2263.
［26］Naz S, Sowers A, Choudhuri R, et al. Abemaciclib, a selective CDK4/6 inhibitor, enhances the radiosensitivity of non-small cell lung cancer in vitro and in vivo［J］. Clin Cancer Res, 2018, 24(16): 3994-4005.
［27］Asghar U, Witkiewicz AK, Turner NC, et al.The history and future of targeting cyclin-dependent kinases in cancer therapy［J］. Nat Rev Drug Discov, 2015, 14(2): 130-146.
［28］Choo JR, Lee SC. CDK4-6 inhibitors in breast cancer: current status and future development［J］.Expert Opin Drug Metab Toxicol，2018，14(11):1123-1138.
［29］Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer［J］. N Engl J Med, 2016, 375(18): 1738-1748.
［30］Knudsen ES, Witkiewicz AK.The Strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies［J］. Trends Cancer, 2017, 3(1): 39-55.
［31］Condorelli R, Spring L, O'shaughnessy J, et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer［J］. Ann Oncol, 2018, 29(3): 640-645.
［32］Li Z, Razavi P, Li Q, et al. Loss of the FAT1 tumor suppressor promotes resistance to cdk4/6 inhibitors via the hippo pathway［J］. Cancer Cell, 2018, 34(6): 893-905.e898.
［33］Olmez I, Zhang Y, Manigat L, et al. Combined c-Met/Trk Inhibition overcomes resistance to cdk4/6 inhibitors in glioblastoma［J］. Cancer Res, 2018, 78(15): 4360-4369.

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靶向抑制CDK4/6的肿瘤治疗基础研究与临床应用进展

Progress in basic research and clinical application of CDK4/6 inhibitor in tumor therapy

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