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细胞周期依赖性激酶4/6抑制剂在恶性肿瘤治疗中的应用及耐药机制

唐辉 应红艳 白春梅

唐辉, 应红艳, 白春梅. 细胞周期依赖性激酶4/6抑制剂在恶性肿瘤治疗中的应用及耐药机制[J]. 协和医学杂志, 2020, 11(6): 758-765. doi: 10.3969/j.issn.1674-9081.2020.06.022
引用本文: 唐辉, 应红艳, 白春梅. 细胞周期依赖性激酶4/6抑制剂在恶性肿瘤治疗中的应用及耐药机制[J]. 协和医学杂志, 2020, 11(6): 758-765. doi: 10.3969/j.issn.1674-9081.2020.06.022
TANG Hui, YING Hong-yan, BAI Chun-mei. Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance[J]. Medical Journal of Peking Union Medical College Hospital, 2020, 11(6): 758-765. doi: 10.3969/j.issn.1674-9081.2020.06.022
Citation: TANG Hui, YING Hong-yan, BAI Chun-mei. Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance[J]. Medical Journal of Peking Union Medical College Hospital, 2020, 11(6): 758-765. doi: 10.3969/j.issn.1674-9081.2020.06.022

细胞周期依赖性激酶4/6抑制剂在恶性肿瘤治疗中的应用及耐药机制

doi: 10.3969/j.issn.1674-9081.2020.06.022
基金项目: 

中国医学科学院医学与健康科技创新工程 2016-12M-1-001

详细信息
    通讯作者:

    应红艳  电话:010-69158764, E-mail:yinghy15@163.com

  • 中图分类号: R73

Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance

Funds: 

Medical and Health Science and Technology Innovation Engineering, Chinese Academy of Medical Sciences 2016-12M-1-001

More Information
    Corresponding author: YING Hong-yan  Tel: 86-10-69158764, E-mail:yinghy15@163.com
  • 摘要: 增殖失控是恶性肿瘤的重要特征之一。细胞周期依赖性激酶4/6(cyclin-dependent kinase 4/6, CDK4/6)抑制剂能作用于各种原因导致的过度活化的CDK4/6,恢复正常细胞周期,并可通过增强免疫、改变肿瘤微环境等发挥抗肿瘤作用。目前,CDK4/6抑制剂在激素受体阳性乳腺癌治疗中取得了良好疗效,已被批准联合内分泌治疗作为此类肿瘤的一线治疗方案,在其他肿瘤中的应用亦逐渐开展,疗效有待验证。对CDK4/6抑制剂天然或获得性耐药是影响其疗效的重要因素,目前激素受体阳性(主要为雌激素受体阳性)能较为准确预测内分泌联合CDK4/6抑制剂治疗的反应性,其他标志物需进一步探索和验证。本文对CDK4/6抑制剂治疗恶性肿瘤的作用机制、应用现状及耐药机制进行梳理和总结,并对当前CDK4/6抑制剂治疗乳腺癌尚存争议的临床决策问题作简要讨论。
    作者贡献:唐辉负责文献检索、数据分析、示意图绘制、论文撰写;应红艳参与文献检索、数据分析、论文修改;白春梅提供修改建议并帮助修改论文。
    利益冲突  无
  • 图  1  细胞周期依赖性激酶4/6调节细胞周期进程及其活性影响因素示意图

    PTEN:10号染色体上缺失的磷酸酶与张力蛋白同源物蛋白;FGFR1:纤维细胞生长因子受体1;MAPK:丝裂原活化蛋白激酶;PI3K:磷脂酰肌醇3-激酶;Akt:蛋白激酶B;mTOR:哺乳动物雷帕霉素靶蛋白;AP-1:激活蛋白-1;cyclin:细胞周期蛋白;CDK:细胞周期依赖性激酶;INK4:CDK4抑制因子;CIP/KIP:CDK相互作用蛋白/激酶抑制蛋白;MDM2:鼠双微基因2;RB1:视网膜母细胞瘤蛋白1;E2F:腺病毒2区早期结合因子;FAT1:脂肪非典型钙黏蛋白1

  • [1] Chong QY, Kok ZH, Bui NL, et al. A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib[J]. Pharmacol Res, 2020, 156: 104686. doi:  10.1016/j.phrs.2020.104686.
    [2] 国家药品监督管理局.中国上市药品目录集[EB/OL]. (2018-07-31).http://202.96.26.102/index/detail/id/511.
    [3] Spring LM, Wander SA, Andre F, et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future[J]. Lancet, 2020, 395: 817-827. doi:  10.1016/S0140-6736(20)30165-3
    [4] Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer[J]. Cancer Treat Rev, 2016, 45: 129-138. doi:  10.1016/j.ctrv.2016.03.002
    [5] Rane SG, Dubus P, Mettus RV, et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia[J]. Nat Genet, 1999, 22: 44-52. doi:  10.1038/8751
    [6] Malumbres M, Sotillo R, Santamaría D, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6[J]. Cell, 2004, 118: 493-504. doi:  10.1016/j.cell.2004.08.002
    [7] Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft[J]. Drug Metab Dispos, 2015, 43: 1360-1371. doi:  10.1124/dmd.114.062745
    [8] Klein ME, Kovatcheva M, Davis LE, et al. CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought[J]. Cancer Cell, 2018, 34: 9-20. doi:  10.1016/j.ccell.2018.03.023
    [9] Vijayaraghavan S, Karakas C, Doostan I, et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers[J]. Nat Commun, 2017, 8: 15916. doi:  10.1038/ncomms15916
    [10] Franco J, Balaji U, Freinkman E, et al. Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities[J]. Cell Rep, 2016, 14: 979-990. doi:  10.1016/j.celrep.2015.12.094
    [11] Wang H, Nicolay BN, Chick JM, et al. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival[J]. Nature, 2017, 546: 426-430. doi:  10.1038/nature22797
    [12] Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity[J]. Nature, 2017, 548: 471-475. doi:  10.1038/nature23465
    [13] Deng J, Wang ES, Jenkins RW, et al. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation[J]. Cancer Discov, 2018, 8: 216-233. doi:  10.1158/2159-8290.CD-17-0915
    [14] Zhang J, Bu X, Wang H, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance[J]. Nature, 2018, 553: 91-95. doi:  10.1038/nature25015
    [15] Hart CD, Migliaccio I, Malorni L, et al. Challenges in the management of advanced, ER-positive, HER2-negative breast cancer[J]. Nat Rev Clin Oncol, 2015, 12: 541-552. doi:  10.1038/nrclinonc.2015.99
    [16] Butt AJ, McNeil CM, Musgrove EA, et al. Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E[J]. Endocr Relat Cancer, 2005, 12: S47-S59. doi:  10.1677/erc.1.00993
    [17] Sutherland RL, Musgrove EA. CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease[J]. Breast Cancer Res, 2009, 12:112.
    [18] Network CGA. Comprehensive molecular portraits of human breast tumours[J]. Nature, 2012, 490: 61-70. doi:  10.1038/nature11412
    [19] Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer[J]. N Engl J Med, 2016, 375: 1925-1936. doi:  10.1056/NEJMoa1607303
    [20] Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial[J]. Lancet Oncol, 2016, 17: 425-439. doi:  10.1016/S1470-2045(15)00613-0
    [21] Slamon DJ, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer[J]. N Engl J Med, 2020, 382: 514-524. doi:  10.1056/NEJMoa1911149
    [22] Sledge GW, Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial[J]. JAMA Oncol, 2019, 6: 116-124. http://publikationen.uni-tuebingen.de/xmlui/handle/10900/109078
    [23] Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A Phase Ⅱ Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer[J]. Clin Cancer Res, 2017, 23:5218-5224. doi:  10.1158/1078-0432.CCR-17-0754
    [24] Franco Y, Ramakrishnan V, Vaidya T, et al. A systems pharmacology model to evaluate triple drug combination therapy at overcoming resistance to anti-HER2 therapy in HER2-positive breast cancer[J]. Clin Pharmacol Ther, 2020, 107: S111.
    [25] Shagisultanova E, Chalasani P, Brown-Glaberman UA, et al. Tucatinib, palbociclib, and letrozole in HR+/HER2+ metastatic breast cancer: Report of phase IB safety cohort[J]. J Clin Oncol, 2019, 37: 1029. doi:  10.1200/JCO.2019.37.15_suppl.1029
    [26] Herold CI, Trippa L, Li T, et al. A phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC)[J]. Cancer Res, 2020, 80: SABCS19-P3-14-03.
    [27] Du Q, Guo X, Wang M, et al. The application and prospect of CDK4/6 inhibitors in malignant solid tumors[J]. J Hematol Oncol, 2020, 13: 41. doi:  10.1186/s13045-020-00880-8
    [28] O'Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors[J]. Nat Rev Clin Oncol, 2016, 13: 417-430. doi:  10.1038/nrclinonc.2016.26
    [29] Goldman JW, Mazieres J, Barlesi F, et al. A randomized phase 3 study of abemaciclib versus erlotinib in previously treated patients with stage Ⅳ NSCLC with KRAS mutation: JUNIPER[J]. J Clin Oncol, 2018, 36:9025. doi:  10.1200/JCO.2018.36.15_suppl.9025
    [30] Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors[J]. Cancer Discov, 2016, 6: 740-753. doi:  10.1158/2159-8290.CD-16-0095
    [31] Anders CK, Le Rhun E, Bachelot TD, et al. A phase Ⅱ study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2-metastatic breast cancer (MBC)[J]. J Clin Oncol, 2019, 37: 1017. doi:  10.1200/JCO.2019.37.15_suppl.1017
    [32] Sahebjam S, Le Rhun E, Queirolo P, et al. 331P - A phase Ⅱ study of abemaciclib in patients (pts) with brain metastases (BM) secondary to non-small cell lung cancer (NSCLC) or melanoma (MEL)[J]. Ann Oncol, 2019:30. doi:  10.1093/annonc/mdz242.026.
    [33] 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: 640-645. doi:  10.1093/annonc/mdx784
    [34] Álvarez-Fernández M, Malumbres M. Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition[J]. Cancer Cell, 2020, 37: 514-529. doi:  10.1016/j.ccell.2020.03.010
    [35] McCartney A, Migliaccio I, Bonechi M, et al. Mechanisms of Resistance to CDK4/6 Inhibitors: Potential Implications and Biomarkers for Clinical Practice[J]. Front Oncol, 2019, 9: 666. doi:  10.3389/fonc.2019.00666
    [36] Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review[J]. Int J Cancer, 2019, 145: 1179-1188. doi:  10.1002/ijc.32020
    [37] Laroche-Clary A, Chaire V, Algeo MP, et al. Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas[J]. J Hematol Oncol, 2017, 10: 123. doi:  10.1186/s13045-017-0482-3
    [38] Herrera-Abreu MT, Palafox M, Asghar U, et al. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer[J]. Cancer Res, 2016, 76: 2301-2313. doi:  10.1158/0008-5472.CAN-15-0728
    [39] Michaloglou C, Crafter C, Siersbaek R, et al. Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor-positive Breast Cancer[J]. Mol Cancer Ther, 2018, 17: 908-920. doi:  10.1158/1535-7163.MCT-17-0537
    [40] Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers[J]. Breast Cancer Res, 2016, 18: 17. doi:  10.1186/s13058-015-0661-5
    [41] Costa C, Wang Y, Ly A, et al. PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer[J]. Cancer Discov, 2020, 10: 72-85. http://www.researchgate.net/publication/336355817_PTEN_loss_mediates_clinical_cross-resistance_to_CDK46_and_PI3Ka_inhibitors_in_breast_cancer
    [42] Yang C, Li Z, Bhatt T, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence[J]. Oncogene, 2017, 36: 2255-2264. doi:  10.1038/onc.2016.379
    [43] Shaulian E, Karin M. AP-1 in cell proliferation and survival[J]. Oncogene, 2001, 20: 2390-2400. doi:  10.1038/sj.onc.1204383
    [44] Teh JLF, Aplin AE. Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment[J]. Clin Cancer Res, 2019, 25: 921-927. doi:  10.1158/1078-0432.CCR-18-1967
    [45] Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro[J]. Breast Cancer Res, 2009, 11: R77. doi:  10.1186/bcr2419
    [46] Turner NC, Liu Y, Zhu Z, et al. Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer[J]. J Clin Oncol, 2019, 37: 1169-1178. doi:  10.1200/JCO.18.00925
    [47] Formisano L, Lu Y, Servetto A, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer[J]. Nat Commun, 2019, 10: 1373. doi:  10.1038/s41467-019-09068-2
    [48] Li J, Fu F, Yu L, et al. Cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer: a meta-analysis of randomized clinical trials[J]. Breast Cancer Res Treat, 2020, 180: 21-32. doi:  10.1007/s10549-020-05528-2
    [49] André F, Ciruelos EM, Juric D, et al. Overall survival (os) results from SOLAR-1, a phase Ⅲ study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC)[J]. Ann Oncol, 2020, 31: S1150-S1151. doi:  10.1016/j.annonc.2020.08.2246
    [50] Turner S, Chia SKL, Kanakamedala H, et al. Real-world effectiveness of alpelisib (ALP) + fulvestrant (FUL) compared with standard treatment among patients (Pts) with hormone-receptor positive (HR+) human epidermal growth factor receptor-2 negative (HER2-) PIK3CA-mutated (Mut) advanced breast cancer (ABC)[J]. Ann Oncol, 2020, 31: S366.
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  • 收稿日期:  2020-06-05
  • 录用日期:  2020-07-20
  • 刊出日期:  2020-11-30

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