title: The history and future of targeting cyclin-dependent kinases in cancer therapy.
abstract: Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.
authors: Breakthrough Breast Cancer Research Centre, Chester Beatty Laboratories, Institute of Cancer Research, London, SW3 6JB, UK.
authors: Uzma
authors: U
authors: Asghar
authors: Simmons Cancer Center and Department of Pathology, University of Texas Southwestern, Dallas, USA.
authors: Agnieszka K
authors: AK
authors: Witkiewicz
authors: Institute of Cancer Research and Royal Marsden NHS Foundation Trust Breast Cancer Unit, London, SW3 6JJ, UK.
authors: Nicholas C
authors: NC
authors: Turner
authors: Simmons Cancer Center and Department of Pathology, University of Texas Southwestern, Dallas, USA.
authors: Erik S
authors: ES
authors: Knudsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases
references: Nature. 1996 Dec 5;384(6608):470-4
references: 8945475
references: Biosci Rep. 2002 Oct-Dec;22(5-6):487-99
references: 12635846
references: BMC Cancer. 2014 Jan 20;14:32
references: 24444383
references: Cancer Res. 1993 Nov 15;53(22):5535-41
references: 8221695
references: Cancer Res. 2009 Feb 1;69(3):810-8
references: 19155308
references: Cancer Cell. 2010 Jul 13;18(1):63-73
references: 20609353
references: J Med Chem. 2004 Mar 25;47(7):1719-28
references: 15027863
references: Clin Cancer Res. 2013 Nov 15;19(22):6173-82
references: 24045179
references: Mol Cancer Ther. 2014 Sep;13(9):2184-93
references: 25028469
references: Mol Cell Biol. 1996 May;16(5):2402-7
references: 8628308
references: Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8871-5
references: 7568034
references: Mol Cancer Ther. 2012 Oct;11(10):2138-48
references: 22869556
references: Biosci Rep. 2002 Jun-Aug;22(3-4):373-94
references: 12516780
references: Cancer Res. 2014 Feb 15;74(4):1141-52
references: 24366882
references: Cancer Cell. 2013 Oct 14;24(4):499-511
references: 24135281
references: Cancer Cell. 2012 Oct 16;22(4):438-51
references: 23079655
references: J Clin Oncol. 1998 Sep;16(9):2986-99
references: 9738567
references: Clin Breast Cancer. 2014 Jun;14(3):169-76
references: 24393852
references: Nature. 1993 Dec 16;366(6456):704-7
references: 8259215
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3761-6
references: 21321214
references: Mol Cell Biol. 2005 May;25(9):3752-62
references: 15831479
references: Clin Cancer Res. 2011 Jul 1;17(13):4513-22
references: 21593195
references: Adv Cancer Res. 1994;64:25-85
references: 7879661
references: Cell. 1997 Mar 7;88(5):593-602
references: 9054499
references: Exp Cell Res. 1997 Nov 25;237(1):1-6
references: 9417859
references: Br J Cancer. 2009 Apr 7;100(7):1055-60
references: 19293801
references: Genes Dev. 1998 Aug 1;12(15):2278-92
references: 9694794
references: Nature. 2000 Sep 7;407(6800):102-6
references: 10993082
references: J Clin Oncol. 2013 Jun 1;31(16):2024-8
references: 23569312
references: Blood. 2012 May 17;119(20):4597-607
references: 22383795
references: Endocr Relat Cancer. 2011 Apr 28;18(3):333-45
references: 21367843
references: Nature. 2005 Aug 4;436(7051):720-4
references: 16079850
references: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5544-9
references: 11331764
references: Nature. 2014 Jun 19;510(7505):393-6
references: 24870234
references: Lung Cancer. 2014 Feb;83(2):219-23
references: 24388167
references: Nat Rev Cancer. 2013 Aug;13(8):585-95
references: 23842645
references: Cancer Res. 2008 Jul 15;68(14):5519-23
references: 18632601
references: Breast Cancer Res. 2009;11(5):R77
references: 19874578
references: J Natl Cancer Inst. 2012 Mar 21;104(6):476-87
references: 22302033
references: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11173-8
references: 8855328
references: Oncotarget. 2014 Aug 15;5(15):6512-25
references: 25156567
references: J Mol Biol. 1999 Apr 16;287(5):821-8
references: 10222191
references: Nat Rev Cancer. 2008 Sep;8(9):671-82
references: 18650841
references: J Biol Chem. 2006 Sep 1;281(35):25644-51
references: 16815849
references: J Transl Med. 2013 Oct 16;11:259
references: 24131779
references: Cancer Discov. 2012 Jun;2(6):524-39
references: 22628408
references: J Cell Biol. 2001 Mar 5;152(5):945-58
references: 11238451
references: Nature. 2001 Jun 28;411(6841):1017-21
references: 11429595
references: Nature. 1995 Jul 27;376(6538):358-62
references: 7630405
references: Genes Dev. 1997 Apr 15;11(8):957-72
references: 9136925
references: Nature. 1995 Jun 8;375(6531):503-6
references: 7777060
references: Cell Cycle. 2006 Oct;5(19):2198-202
references: 16969100
references: Curr Opin Cell Biol. 1998 Dec;10(6):776-83
references: 9914175
references: Exp Cell Res. 1996 Dec 15;229(2):174-80
references: 8986594
references: Science. 1993 Dec 24;262(5142):2050-4
references: 8266103
references: Ann Oncol. 2010 Apr;21(4):884-894
references: 19825886
references: Nat Cell Biol. 1999 Jun;1(2):E47-53
references: 10559897
references: Nat Immunol. 2006 May;7(5):489-97
references: 16582912
references: Genes Dev. 2002 Dec 15;16(24):3277-89
references: 12502747
references: Lancet Oncol. 2015 Jan;16(1):25-35
references: 25524798
references: Genes Dev. 1999 Jun 15;13(12):1501-12
references: 10385618
references: Harvey Lect. 2000-2001;96:73-92
references: 12200872
references: Biochimie. 2014 Feb;97:22-7
references: 24139904
references: Mol Cell Biol. 2005 Dec;25(24):10875-94
references: 16314512
references: Genes Dev. 1995 Aug 1;9(15):1831-45
references: 7649471
references: Trends Biochem Sci. 1995 May;20(5):187-90
references: 7610482
references: Curr Opin Cell Biol. 2001 Dec;13(6):748-53
references: 11698192
references: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1682-6
references: 11172011
references: Cell. 2000 Sep 29;103(1):127-40
references: 11051553
references: Autophagy. 2013 Mar;9(3):434-5
references: 23422081
references: Leukemia. 2011 Sep;25(9):1444-51
references: 21606960
references: Int J Cancer. 2010 Aug 15;127(4):961-7
references: 19957331
references: Front Biosci. 2000 Feb 01;5:D244-57
references: 10704151
references: Mol Cancer Ther. 2014 Oct;13(10):2253-63
references: 25122067
references: Cell. 1994 Jul 15;78(1):59-66
references: 8033212
references: Invest New Drugs. 2008 Feb;26(1):59-65
references: 17938863
references: Cell. 1991 May 17;65(4):701-13
references: 1827757
references: Clin Transl Oncol. 2006 Jun;8(6):399-408
references: 16790392
references: Clin Cancer Res. 2014 Jul 15;20(14):3763-74
references: 24850847
references: Genes Dev. 2000 Sep 15;14(18):2298-313
references: 10995387
references: Mol Cell Biol. 1994 Mar;14(3):2066-76
references: 8114738
references: Cell Death Differ. 2013 Jun;20(6):800-11
references: 23429262
references: Leuk Lymphoma. 2013 Oct;54(10):2133-43
references: 23488658
references: Nat Rev Cancer. 2001 Dec;1(3):222-31
references: 11902577
references: Cell Cycle. 2012 Jul 15;11(14):2747-55
references: 22751436
references: Cancer Discov. 2011 Sep;1(4):338-51
references: 22049316
references: Breast Cancer Res Treat. 2020 Sep;183(2):419-428
references: 32683565
references: Cancer Res. 2004 Dec 15;64(24):8954-9
references: 15604258
references: Nat Rev Drug Discov. 2009 Jul;8(7):547-66
references: 19568282
references: Genes Dev. 2002 Jan 15;16(2):245-56
references: 11799067
references: Oncogene. 2006 Mar 13;25(11):1620-8
references: 16550162
references: Lancet Oncol. 2008 Oct;9(10):937-45
references: 18783988
references: Cancer Res. 2004 Jan 1;64(1):262-72
references: 14729633
references: Oncogene. 2001 Apr 5;20(15):1803-15
references: 11313928
references: J Clin Oncol. 2010 Jan 20;28(3):418-23
references: 20008633
references: Clin Cancer Res. 2012 Jan 15;18(2):568-76
references: 22090362
references: Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19489-94
references: 24218601
references: Invest New Drugs. 2014 Oct;32(5):825-37
references: 24919854
references: J Clin Oncol. 2003 May 1;21(9):1740-5
references: 12735303
references: Mol Cell Biol. 1995 May;15(5):2600-11
references: 7739541
references: Br J Cancer. 2011 Jun 7;104(12):1862-8
references: 21610706
references: Nature. 2009 Nov 5;462(7269):108-12
references: 19847166
references: Cancer Discov. 2014 Aug;4(8):OF2
references: 25092757
references: PLoS One. 2013 Oct 02;8(10):e77639
references: 24098593
references: Oncogene. 2013 Nov 28;32(48):5481-91
references: 23708653
references: Dev Cell. 2010 Apr 20;18(4):533-43
references: 20412769
references: J Clin Oncol. 2010 Jun 20;28(18):3015-22
references: 20479412
references: Oncogene. 2010 Jul 15;29(28):4018-32
references: 20473330
references: Cancer Res. 2002 Nov 15;62(22):6587-97
references: 12438254
references: Mol Cancer Ther. 2006 Nov;5(11):2644-58
references: 17121911
references: Cancer Biol Ther. 2002 May-Jun;1(3):226-31
references: 12432268
references: Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1091-6
references: 9448290
references: Cancer Res. 2006 Apr 15;66(8):4299-308
references: 16618755
references: EMBO J. 2004 Nov 24;23(23):4615-26
references: 15510213
references: Nat Rev Cancer. 2008 Sep;8(9):714-24
references: 19143056
references: Oncotarget. 2014 Jan 30;5(2):375-85
references: 24495868
references: Philos Trans R Soc Lond B Biol Sci. 2011 Dec 27;366(1584):3494-7
references: 22084376
references: Cancer Cell. 2014 Jul 14;26(1):136-49
references: 25002028
references: Cancer Res. 1992 May 15;52(10):2980-3
references: 1533816
references: Nature. 2008 Sep 25;455(7212):547-51
references: 18794900
references: Cancer Cell. 2011 Nov 15;20(5):620-34
references: 22094256
references: Oncogene. 2004 Mar 15;23(11):2016-27
references: 15021889
references: Cell. 2013 Jan 17;152(1-2):340-51
references: 23332765
references: Cancer Res. 2010 Apr 15;70(8):3228-38
references: 20354191
references: Mod Pathol. 2014 Jul;27(7):1014-9
references: 24309323
references: Cell Cycle. 2012 Jul 15;11(14):2756-61
references: 22767154
references: Cell. 1993 Nov 19;75(4):817-25
references: 8242752
references: Genes Dev. 2000 Dec 15;14(24):3115-25
references: 11124804
references: J Clin Oncol. 2006 Apr 10;24(11):1770-83
references: 16603719
references: Pigment Cell Melanoma Res. 2014 Jul;27(4):590-600
references: 24495407
references: Mol Cancer Ther. 2010 Aug;9(8):2344-53
references: 20663931
references: Genes Dev. 2012 Mar 1;26(5):474-89
references: 22391450
references: Cell. 1987 Jul 17;50(2):319-25
references: 3297353
references: Mol Cancer Ther. 2004 Nov;3(11):1427-38
references: 15542782
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11501-6
references: 20534551
references: Anticancer Res. 2013 Aug;33(8):2997-3004
references: 23898052
references: Mol Cell Biol. 2001 Jun;21(12):4032-45
references: 11359910
references: Nature. 1991 Apr 11;350(6318):512-5
references: 1826542
references: Nat Med. 2012 Oct;18(10):1503-10
references: 22983396
references: Nature. 2014 Jul 31;511(7511):616-20
references: 25043025
references: Cell Cycle. 2005 Mar;4(3):388-91
references: 15738651
references: Cell. 2004 Aug 20;118(4):493-504
references: 15315761
references: Biosci Rep. 2002 Oct-Dec;22(5-6):465-86
references: 12635845
references: Genes Dev. 1997 Jun 1;11(11):1479-92
references: 9192874
references: Cell Cycle. 2011 Aug 1;10(15):2497-503
references: 21775818
references: Int J Oncol. 1996 Dec;9(6):1143-68
references: 21541623
references: Nat Med. 2011 Jun 26;17(7):875-82
references: 21706030
references: Genes Dev. 2014 Aug 15;28(16):1800-14
references: 25128497
references: Genes Dev. 1994 Jan;8(1):9-22
references: 8288131
references: Cell. 2004 Aug 20;118(4):477-91
references: 15315760
references: Blood. 2007 Jan 15;109(2):399-404
references: 17003373
references: Nature. 2006 Nov 30;444(7119):633-7
references: 17136093
references: Expert Opin Investig Drugs. 2000 Dec;9(12):2903-11
references: 11093360
references: Cancer Res. 2001 Oct 1;61(19):7325-32
references: 11585773
references: Genes Cancer. 2014 Jul;5(7-8):261-72
references: 25221644
references: Gastroenterology. 2010 May;138(5):1920-30
references: 20100483
references: Int J Biochem Cell Biol. 2004 Aug;36(8):1424-39
references: 15147722
references: J Neurooncol. 2013 Jan;111(2):113-21
references: 23138228
references: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6488-93
references: 8692842
references: Oncogene. 2005 Oct 27;24(47):7114-9
references: 16103884
references: N Engl J Med. 2009 Jan 22;360(4):423-4
references: 19164198
references: J Biol Chem. 2012 Aug 17;287(34):29075-87
references: 22733811
references: Cancer Res. 2014 Jul 15;74(14):3947-58
references: 24986516
references: Genes Dev. 1993 Mar;7(3):331-42
references: 8449399
references: Mol Cancer Ther. 2009 Jul;8(7):1856-66
references: 19509270
references: Cancer Res. 1996 Jul 1;56(13):2973-8
references: 8674031
references: Clin Cancer Res. 2014 Jul 1;20(13):3379-83
references: 24795392
references: Mol Cancer Res. 2014 Feb;12(2):167-83
references: 24136988
references: Eur J Cancer. 2010 Dec;46(18):3243-50
references: 20822897
references: Sci Rep. 2014 Jan 10;4:3623
references: 24406431
references: Future Oncol. 2010 Dec;6(12):1837-47
references: 21142858
references: Nat Med. 1998 Oct;4(10):1103-6
references: 9771732
references: J Med Chem. 2005 Apr 7;48(7):2388-406
references: 15801831
references: Clin Cancer Res. 2011 Mar 15;17(6):1591-602
references: 21278246
references: Nature. 1998 Sep 17;395(6699):237-43
references: 9751050
references: Nature. 2007 Aug 16;448(7155):811-5
references: 17700700
references: Cancer Cell. 2012 Oct 16;22(4):452-65
references: 23079656
references: J Med Chem. 2005 Apr 7;48(7):2371-87
references: 15801830
references: Science. 1996 Dec 6;274(5293):1672-7
references: 8939849
references: Blood. 2006 Sep 1;108(5):1744-50
references: 16690963
references: Nat Rev Mol Cell Biol. 2001 Jan;2(1):21-32
references: 11413462
references: Genes Dev. 1993 Aug;7(8):1572-83
references: 8101826
references: Expert Opin Investig Drugs. 2013 Jun;22(6):723-38
references: 23647051
references: J Cell Biol. 2010 Apr 19;189(2):247-59
references: 20404109
references: Int J Cancer. 1994 May 1;57(3):353-61
references: 8168995
references: Development. 2013 Aug;140(15):3079-93
references: 23861057
references: Genes Dev. 1998 Nov 15;12(22):3499-511
references: 9832503
references: Mol Cancer Ther. 2012 Jul;11(7):1488-99
references: 22564725
references: Oncogene. 1993 Aug;8(8):2127-33
references: 8336939
references: Nat Rev Cancer. 2008 Apr;8(4):253-67
references: 18354415