CDK4/6抑制剂联合mTOR抑制剂在乳腺癌中的作用机制

doi:10.11904/j.issn.1002-3070.2019.05.018

摘要/Abstract

摘要： CDK-RB-E2F通路和PI3K-AKT-mTOR通路对乳腺癌耐药机制起到了关键作用。通过对两个通路的研究发现,在治疗激素受体阳性的乳腺癌时,CDK4/6抑制剂与内分泌药物联合使用可以提高患者的生存率,mTOR抑制剂也显示出抗肿瘤的实力。最近的研究表明,mTOR抑制剂和CDK4/6抑制剂联合使用可以进一步抑制CDK-RB-E2F通路激活,协同控制肿瘤细胞增殖。同时发现CDK4/6抑制剂耐药患者的CDK-RB-E2F通路重新激活,仍对mTOR抑制剂敏感。还有研究表明CDK4/6抑制剂和mTOR抑制剂可以通过自噬作用协同控制肿瘤的发生。本文针对两药联合在乳腺癌中的作用机制进行综述。

关键词: CDK4/6抑制剂, mTOR抑制剂, E2F, 视网膜母细胞瘤, 乳腺癌, 自噬

Abstract: Many studies indicate that the CDK-RB-E2F pathway and the PI3K-AKT-mTOR pathway play key roles in the mechanism of drug resistance in breast cancer.Through studies of two pathways,the combination of CDK4/6 inhibitors and endocrine drugs can improve the survival rate of patients with hormone receptor-positive breast cancer,and mTOR inhibitors also show the anti-tumor strength.Recent studies have shown that the combination of mTOR inhibitors and CDK4/6 inhibitors can further inhibit the activation of the CDK-RB-E2F pathway and synergistically controls tumor cell proliferation.It was also found that the CDK-RB-E2F pathway in CDK4/6 inhibitor-resistant patients was reactivated and sensitive to mTOR inhibitor.Other studies have also shown that CDK4/6 inhibitors and mTOR inhibitors can synergistically control tumorigenesis through autophagy.This article reviews several mechanisms of combination of two drugs.

Key words: CDK4/6 inhibitors, mTOR inhibitors, E2F, RB, Breast cancer, Autophagy

中图分类号:

R737.9

刘尔钰, 杨昊, 梁国华, 赵晏方, 赵文辉. CDK4/6抑制剂联合mTOR抑制剂在乳腺癌中的作用机制[J]. 实用肿瘤学杂志, 2019, 33(5): 476-480.

LIU Eryu, YANG Hao, LIANG Guohua, ZHAO Yanfang, ZHAO Wenhui. Action for CDK4/6 inhibitors combined with mTOR inhibitors in breast cancer and its mechanism[J]. Journal of Practical Oncology, 2019, 33(5): 476-480.

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链接本文: http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/10.11904/j.issn.1002-3070.2019.05.018

http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/Y2019/V33/I5/476

参考文献

1 Coates AS,Winer EP,Goldhirsch A,et al.Tailoring therapies-improving the management of early breast cancer:St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015[J].Ann Oncol,2015,26(8):1533-1546.
2 Early Breast Cancer Trialists′ Collaborative Group.Aromatase inhibitors versus tamoxifen in early breast cancer:patient-level meta-analysis of the randomised trials[J].Lance,2015,386(10001):1341-1352.
3 Wilson S,Chia SK.Treatment algorithms for hormone receptorpositive advanced breast cancer:applying the results from recent clinical trials into daily practice-insights,limitations,and moving forward[J].Am Soc Clin Oncol Educ Book,2013,2013:20-27.
4 Tripathy D.The BMC medicine breast cancer collection:an illustration of contemporary research and clinical care[J].BMC Medicine,2015,13:223.
5 Bevers TB,Helvie M,Bonaccio E,et al.Breast cancer screening and diagnosis,version 3.2018,NCCN clinical practice guidelines in oncology[J].J Natl Compr Canc Netw,2018,16(11):1362-1389.
6 Laplante M,Sabatini DM.mTOR signaling in growth control and disease[J].Cell,2012,149(2):274-293.
7 Yip CK,Murata K,Walz T,et al.Structure of the human mTOR complex I and its implications for rapamycin inhibition[J].Molecular Cell,2010,38(5):768-774.
8 Pardee AB.A Restriction point for control of normal animal cell proliferation[J].Proc Natl Acad Sci U S A,1974,71(4):1286-1290.
9 Chumsri S,Sabnis G,Tkaczuk K,et al.mTOR inhibitors:changing landscape of endocrine-resistant breast cancer[J].Future Oncol,2014,10(3):443-456.
10 Baselga J,Campone M,Piccart M,et al.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer[J].N Engl J Med,2012,366(6):520-529.
11 Hortobagyi GN,Chen D,Piccart M,et al.Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer:results from BOLERO-2[J].J Clin Oncol,2016,34(5):419-426.
12 Yardley DA,Noguchi S,Pritchard KI,et al.Everolimus plus exemestane in postmenopausal patients with HR+Breast Cancer:BOLERO-2 final progression-free survival analysis[J].Adv Ther,2013,30(10):870-884.
13 Michaloglou C,Crafter C,Sierbaek 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(5),908-920.
14 Hortobagyi GN,Stemmer SM,Burris HA,et al.Updated results from MONALEESA-2,a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive,HER2-negative advanced breast cancer[J].Ann Oncol,2018,29(7):1541-1547.
15 Guichard SM,Curwen J,Bihani T,et al.AZD2014,an inhibitor of mTORC1 and mTORC2,Is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules[J].Mol Cancer Ther,2015,14(11):2508-2518.
16 Finn RS,Martin M,Rugo HS,et al.Palbociclib and Letrozole in advanced breast cancer[J].N Engl J Med,2016,375(20):1925-1936.
17 Thurlings I,de Bruin A.E2F transcription factors control the roller coaster ride of cell cycle gene expression[J].Methods Mol Biol,2016,1342:71-88.
18 Zhang J,Xu K,Liu P,et al.Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt[J].Mol Cell,2016,62(6):929-942.
19 Bonelli MA,Digiacomo G,Fumarola C,et al.Combined inhibition of CDK4/6 and PI3K/AKT/mTOR pathways induces a synergistic anti-tumor effect in malignant pleural mesothelioma cells[J].Neoplasia,2017,19(8):637-648.
20 Perez-Mancera PA,Young AR,Narita M.Inside and out:the activities of senescence in cancer[J].Nat Rev Cancer,2014,14(8):547-558.
21 Otto T,Sicinski P.Cell cycle proteins as promising targets in cancer therapy[J].Nat Rev Cancer,2017,17(2):93-115.
22 Debacq-Chainiaux F,Erusalimsky JD,Campisi J,et al.Protocols to detect senescence-associated beta-galactosidase(SA-betagal)activity,a biomarker of senescent cells in culture and in vivo[J].Nat Protoc,2009,4(12):1798-1806.
23 Tomimatsu K,Narita M.Translating the effects of mTOR on secretory senescence[J].Nat Cell Biol,2015,17(10):1230-1232.
24 Wang W,Dong L,Saville B,et al.Transcriptional activation ofE2F1gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions[J].Mol Endocrinol,1999,13(8):1373-1387.
25 Bahri A,Li Z,Morel JM,et al.PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer[J].Sci Transl Med,2015,7(283):283ra51.
26 Alayev A,Salamon RS,Berger SM,et al.mTORC1 directly phosphorylates and activates ERa upon estrogen stimulation[J].Oncogene,2015,35:3535-3543.
27 Yamnik RL,Digilova A,Davis DC,et al.S6 Kinase 1 regulates estrogen receptor in control of breast cancer cell proliferation[J].J Biol Chem,2009,284(10):6361-6369.
28 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(8):2301-2313.
29 Sherr CJ,Beach D,Shapiro GI.Targeting CDK4 and CDK6:from discovery to therapy[J].Cancer Discovery,2016,6(4):353-367.
30 O′Leary B,Finn RS,Turner NC.Treating cancer with selective CDK4/6 inhibitors[J].Nature Reviews Clinical Oncology,2016,13(7):417-430.
31 Johnson J,Thijssen B,McDermott U,et al.Targeting the RB-E2F pathway in breast cancer[J].Oncogene,2016,35(37):4829-4835.
32 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(16):2255-2264.
33 Jansen VM,Bhola NE,Bauer JA,et al.Kinome-Wide RNA interference screen revealsa role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer[J].Cancer Res,2017,77(9):2488-2499.
34 Knudsen ES,Witkiewicz AK.The strange case of CDK4/6 inhibitors:mechanisms,resistance,and combination strategies[J].Trends Cancer,2017,3(1):39-55.
35 Yang Z,Klionsky DJ.Eaten alive:a history of macroautophagy[J].Nature Cell Biology,2010,12(9):814-822.
36 Yoshida GJ.Metabolic reprogramming:the emerging concept and associated therapeutic strategies[J].J Exp Clin Cancer Res,2015,34(1):1-10.
37 Fan Y,Dickman KG,Zong WX.Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition[J].J Biol Chem,2010,285(10):7324-7333.
38 Fritz V,Fajas L.Metabolism and proliferation share common regulatory pathways in cancer cells[J].Oncogene,2010,29(31):4369-4377.
39 Fajas L.Re-thinking cell cycle regulators:the cross-talk with metabolism[J].Front Oncol,2013,3(3):4.
40 Olmez I,Brenneman B,Xiao A,et al.Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms[J].Clin Cancer Res,2017,23(22):6958-6968.
41 Deberardinis RJ,Lum JJ,Hatzivassiliou G,et al.The biology of cancer:metabolic reprogramming fuels cell growth and proliferation[J].Cell Metab,2008,7(1):11-20.
42 Sonia Pernas,Sara M,Tolaney,et al.CDK4/6 inhibition in breast cancer:current practice and future directions[J].Ther Adv Med Oncol,2018,10:1758835918786451.

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