The history and future of targeting cyclin-dependent kinases in cancer therapy

Nature Reviews Drug Discovery

Volumn 14, Issue 2, 2015, Pages 130-146

  Asghar, Uzma ^a   Witkiewicz, Agnieszka K ^b   Turner, Nicholas C ^c   Knudsen, Erik S ^b  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ABEMACICLIB; AG 024322; ALPELISIB; AT 7519; AZD 5438; BINIMETINIB; BORTEZOMIB; CAPECITABINE; CDKI 73; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 1; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; CYCLIN DEPENDENT KINASE INHIBITOR; DINACICLIB; ESTROGEN RECEPTOR ANTAGONIST; EVEROLIMUS; EXEMESTANE; FLAVOPIRIDOL; FULVESTRANT; LETROZOLE; N [5 (5 TERT BUTYL 2 OXAZOLYLMETHYLTHIO) 2 THIAZOLYL]ISONIPECOTAMIDE; OLOMUCINE; PALBOCICLIB; PYRIDO[2,3 D]PYRIMIDIN 7 ONE DERIVATIVE; R 547; RIBOCICLIB; ROSCOVITINE; THZ 1; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADVANCED CANCER; ANEMIA; ANTINEOPLASTIC ACTIVITY; BONE MARROW SUPPRESSION; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER HORMONE THERAPY; CARCINOGENESIS; CELL CYCLE PROGRESSION; CELL CYCLE REGULATION; CELL CYCLE S PHASE; CHRONIC LYMPHATIC LEUKEMIA; COLON CANCER; DIARRHEA; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG POTENCY; DRUG RESISTANCE; DRUG RESPONSE; DRUG SCREENING; DRUG SELECTIVITY; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; ENZYME ACTIVATION; ENZYME INHIBITION; ESOPHAGUS CANCER; G2 PHASE CELL CYCLE CHECKPOINT; GASTROINTESTINAL TOXICITY; GLIOBLASTOMA; GLIOMA; HODGKIN DISEASE; HUMAN; IC50; KIDNEY CANCER; LEUKEMIA; LIPOSARCOMA; LIVER CELL CARCINOMA; LUNG ADENOCARCINOMA; LYMPHOBLASTOMA; LYMPHOMA; MANTLE CELL LYMPHOMA; MEDULLOBLASTOMA; MELANOMA; MONOTHERAPY; MULTIPLE MYELOMA; NAUSEA; NEUROBLASTOMA; NEUTROPENIA; NON SMALL CELL LUNG CANCER; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION; SMALL CELL LUNG CANCER; SOLID TUMOR; TESTIS CANCER; UNSPECIFIED SIDE EFFECT;

EID: 84959852003     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4504     Document Type: Review

References (204)

1. Nurse, P., Masui, Y., & Hartwell, L. Understanding the cell cycle. Nature Med. 4, 1103-1106 (1998
2. Sherr, C. J. Cancer cell cycles. Science 274, 1672-1677 (1996
3. Lim, S., & Kaldis, P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 140, 3079-3093 (2013
4. Malumbres, M. Therapeutic opportunities to control tumor cell cycles. Clin. Transl. Oncol. 8, 399-408 (2006
5. Hunt, T., Nasmyth, K., & Novak, B. The cell cycle. Phil. Trans. R. Soc. B 366, 3494-3497 (2011
6. Hunt, T. Nobel Lecture. Protein synthesis, proteolysis, and cell cycle transitions. Biosci. Rep. 22, 465-486 (2002
7. Nurse, P. M. Nobel Lecture. Cyclin dependent kinases and cell cycle control. Biosci. Rep. 22, 487-499 (2002
8. Hartwell, L. H. Nobel Lecture. Yeast and cancer. Biosci. Rep. 22, 373-394 (2002). References 6-8 provide highly insightful overviews of the Nobel Prize-winning findings that underpin much of the subsequent analyses of cell cycle regulatory processes.
9. Drapkin, R., Le Roy, G., Cho, H., Akoulitchev, S., & Reinberg, D. Human cyclin-dependent kinase-Activating kinase exists in three distinct complexes. Proc. Natl Acad. Sci. USA 93, 6488-6493 (1996
10. Bregman, D. B., Pestell, R. G., & Kidd, V. J. Cell cycle regulation and RNA polymerase II. Front. Biosci. 5, D244-D257 (2000
11. Nemet, J., Jelicic, B., Rubelj, I., & Sopta, M. The two faces of Cdk8, a positive/negative regulator of transcription. Biochimie 97, 22-27 (2014
12. Malumbres, M., & Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nature Rev. Cancer 1, 222-231 (2001
13. Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 510, 393-396 (2014
14. Pavletich, N. P. Mechanisms of cyclin-dependent kinase regulation: structures of CDKs, their cyclin activators, and CIP and INK4 inhibitors. J. Mol. Biol. 287, 821-828 (1999
15. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493-504 (2004
16. Hu, M. G. et al. A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res. 69, 810-818 (2009
17. Sherr, C. J. D-type cyclins. Trends Biochem. Sci. 20, 187-190 (1995
18. Diehl, J. A. Cycling to cancer with cyclin D1. Cancer Biol. Ther. 1, 226-231 (2002
19. Matsushime, H., Roussel, M. F., Ashmun, R. A., & Sherr, C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65, 701-713 (1991
20. Spofford, L. S., Abel, E. V., Boisvert-Adamo, K., & Aplin, A. E. Cyclin D3 expression in melanoma cells is regulated by adhesion-dependent phosphatidylinositol 3-kinase signaling and contributes to G1-S progression. J. Biol. Chem. 281, 25644-25651 (2006
21. Sicinski, P. et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384, 470-474 (1996
22. Kushner, J. A. et al. Cyclins D2 and D1 are essential for postnatal pancreatic ?-cell growth. Mol. Cell. Biol. 25, 3752-3762 (2005
23. Yu, Q., Ciemerych, M. A., & Sicinski, P. Ras and Myc can drive oncogenic cell proliferation through individual D-cyclins. Oncogene 24, 7114-7119 (2005
24. Cooper, A. B. et al. A unique function for cyclin D3 in early B cell development. Nature Immunol. 7, 489-497 (2006
25. Ciemerych, M. A. et al. Development of mice expressing a single D-type cyclin. Genes Dev. 16, 3277-3289 (2002
26. Diehl, J. A., Zindy, F., & Sherr, C. J. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev. 11, 957-972 (1997
27. Diehl, J. A., Cheng, M., Roussel, M. F., & Sherr, C. J. Glycogen synthase kinase-3? regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499-3511 (1998
28. Cheng, M., Sexl, V., Sherr, C. J., & Roussel, M. F. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-Activated protein kinase kinase (MEK1). Proc. Natl Acad. Sci. USA 95, 1091-1096 (1998
29. Witkiewicz, A. K., Knudsen, K. E., Dicker, A. P., & Knudsen, E. S. The meaning of p16INK4A expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 10, 2497-2503 (2011
30. Serrano, M., Hannon, G. J., & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704-707 (1993
31. Jeffrey, P. D., Tong, L., & Pavletich, N. P. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Genes Dev. 14, 3115-3125 (2000
32. Russo, A. A., Tong, L., Lee, J. O., Jeffrey, P. D., & Pavletich, N. P. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 395, 237-243 (1998
33. Serrano, M., & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748-753 (2001
34. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602 (1997
35. Reynisdottir, I., Polyak, K., Iavarone, A., & Massague, J. Kip/Cip and INK4 CDK inhibitors cooperate to induce cell cycle arrest in response to TGF-?. Genes Dev. 9, 1831-1845 (1995
36. Terada, Y., Tatsuka, M., Jinno, S., & Okayama, H. Requirement for tyrosine phosphorylation of Cdk4 in G1 arrest induced by ultraviolet irradiation. Nature 376, 358-362 (1995
37. Bertero, T. et al. CDC25A targeting by miR-483-3p decreases CCND-CDK4/6 assembly and contributes to cell cycle arrest. Cell Death Differ. 20, 800-811 (2013
38. Anders, L. et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20, 620-634 (2011
39. Kato, J., Matsushime, H., Hiebert, S. W., Ewen, M. E., & Sherr, C. J. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 7, 331-342 (1993
40. Matsushime, H. et al. D-type cyclin-dependent kinase activity in mammalian cells. Mol. Cell. Biol. 14, 2066-2076 (1994
41. Wang, J. Y., Knudsen, E. S., & Welch, P. J. The retinoblastoma tumor suppressor protein. Adv. Cancer Res. 64, 25-85 (1994
42. Burkhart, D. L., & Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Rev. Cancer 8, 671-682 (2008
43. Knudsen, E. S., & Knudsen, K. E. Tailoring to RB: tumour suppressor status and therapeutic response. Nature Rev. Cancer 8, 714-724 (2008
44. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633-637 (2006
45. Michaloglou, C. et al. BRAFE600-Associated senescence-like cell cycle arrest of human naevi. Nature 436, 720-724 (2005
46. Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell 152, 340-351 (2013
47. LaPak, K. M., & Burd, C. E. The molecular balancing act of p16INK4a in cancer and aging. Mol. Cancer Res. 12, 167-183 (2014
48. Lukas, J. et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503-506 (1995
49. Lukas, J., Bartkova, J., Rohde, M., Strauss, M., & Bartek, J. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol. Cell. Biol. 15, 2600-2611 (1995
50. Motokura, T. et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350, 512-515 (1991
51. Knudsen, K. E., Diehl, J. A., Haiman, C. A., & Knudsen, E. S. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 25, 1620-1628 (2006
52. Jiang, W. et al. Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res. 52, 2980-2983 (1992
53. Buckley, M. F. et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 8, 2127-2133 (1993
54. Bartkova, J. et al. Cyclin D1 protein expression and function in human breast cancer. Int. J. Cancer 57, 353-361 (1994
55. Khatib, Z. A. et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 53, 5535-5541 (1993
56. Park, S. et al. Aberrant CDK4 amplification in refractory rhabdomyosarcoma as identified by genomic profiling. Sci. Rep. 4, 3623 (2014
57. Ma, T. et al. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev. 14, 2298-2313 (2000
58. Okuda, M. et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103, 127-140 (2000
59. Sever-Chroneos, Z. et al. Retinoblastoma tumor suppressor protein signals through inhibition of cyclin-dependent kinase 2 activity to disrupt PCNA function in S phase. Mol. Cell. Biol. 21, 4032-4045 (2001
60. Sherr, C. J., & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501-1512 (1999
61. Herrera, R. E. et al. Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts. Mol. Cell. Biol. 16, 2402-2407 (1996
62. Zhu, W., Giangrande, P. H., & Nevins, J. R. E2Fs link the control of G1/S and G2/M transcription. EMBO J. 23, 4615-4626 (2004
63. Markey, M. P. et al. Unbiased analysis of RB-mediated transcriptional repression identifies novel targets and distinctions from E2F action. Cancer Res. 62, 6587-6597 (2002
64. Moroy, T., & Geisen, C. Cyclin, E. Int. J. Biochem. Cell Biol. 36, 1424-1439 (2004
65. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints. Genes Dev. 16, 245-256 (2002
66. Sherr, C. J. Cell cycle control and cancer. Harvey Lect. 96, 73-92 (2000
67. Bartek, J., Bartkova, J., & Lukas, J. The retinoblastoma protein pathway in cell cycle control and cancer. Exp. Cell Res. 237, 1-6 (1997
68. Xiong, Y., Zhang, H., & Beach, D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 7, 1572-1583 (1993
69. el-Deiry, W. S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817-825 (1993
70. Polyak, K. et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-? and contact inhibition to cell cycle arrest. Genes Dev. 8, 9-22 (1994
71. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59-66 (1994
72. van den Heuvel, S., & Harlow, E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262, 2050-2054 (1993
73. Wu, C. L. et al. Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers. Cancer Res. 61, 7325-7332 (2001
74. Scaltriti, M. et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc. Natl Acad. Sci. USA 108, 3761-3766 (2011
75. Etemadmoghadam, D. et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc. Natl Acad. Sci. USA 110, 19489-19494 (2013
76. Karst, A. M. et al. Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers. Cancer Res. 74, 1141-1152 (2014
77. Kuhn, E., Bahadirli-Talbott, A., & Shih, I. E. M. Frequent CCNE1 amplification in endometrial intraepithelial carcinoma and uterine serous carcinoma. Mod. Pathol. 27, 1014-1019 (2014
78. Caldon, C. E. et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol. Cancer Ther. 11, 1488-1499 (2012
79. Lukas, J. et al. Cyclin E-induced S phase without activation of the pRB/E2F pathway. Genes Dev. 11, 1479-1492 (1997
80. Knudsen, E. S., Buckmaster, C., Chen, T. T., Feramisco, J. R., & Wang, J. Y. Inhibition of DNA synthesis by RB: effects on G1/S transition and S-phase progression. Genes Dev. 12, 2278-2292 (1998
81. Hershko, D. D. Cyclin-dependent kinase inhibitor p27 as a prognostic biomarker and potential cancer therapeutic target. Future Oncol. 6, 1837-1847 (2010
82. Chu, I. M., Hengst, L., & Slingerland, J. M. The CDK inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nature Rev. Cancer 8, 253-267 (2008
83. Draetta, G., Brizuela, L., Potashkin, J., & Beach, D. Identification of p34 and p13, human homologs of the cell cycle regulators of fission yeast encoded by cdc2+ and suc1+. Cell 50, 319-325 (1987
84. Sadasivam, S., Duan, S., & DeCaprio, J. A. The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev. 26, 474-489 (2012
85. Sadasivam, S., & DeCaprio, J. A. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nature Rev. Cancer 13, 585-595 (2013
86. Wang, I. C. et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell. Biol. 25, 10875-10894 (2005
87. Draviam, V. M., Orrechia, S., Lowe, M., Pardi, R., & Pines, J. The localization of human cyclins B1 and B2 determines CDK1 substrate specificity and neither enzyme requires MEK to disassemble the Golgi apparatus. J. Cell Biol. 152, 945-958 (2001
88. Gavet, O., & Pines, J. Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis. Dev. Cell 18, 533-543 (2010
89. Gavet, O., & Pines, J. Activation of cyclin B1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis. J. Cell Biol. 189, 247-259 (2010
90. Nigg, E. A. Polo-like kinases: positive regulators of cell division from start to finish. Curr. Opin. Cell Biol. 10, 776-783 (1998
91. Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448, 811-815 (2007
92. Aarts, M. et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2, 524-539 (2012
93. Nigg, E. A. Mitotic kinases as regulators of cell division and its checkpoints. Nature Rev. Mol. Cell Biol. 2, 21-32 (2001
94. Nigg, E. A., Blangy, A., & Lane, H. A. Dynamic changes in nuclear architecture during mitosis: on the role of protein phosphorylation in spindle assembly and chromosome segregation. Exp. Cell Res. 229, 174-180 (1996
95. Bharadwaj, R., & Yu, H. The spindle checkpoint, aneuploidy, and cancer. Oncogene 23, 2016-2027 (2004
96. Morgan, D. O. Regulation of the APC and the exit from mitosis. Nature Cell Biol. 1, E47-E53 (1999
97. Taylor, W. R., & Stark, G. R. Regulation of the G2/M transition by p53. Oncogene 20, 1803-1815 (2001
98. Bayart, E., Grigorieva, O., Leibovitch, S., Onclercq-Delic, R., & Amor-Gueret, M. A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint. Cancer Res. 64, 8954-8959 (2004
99. Aaltonen, K. et al. High cyclin B1 expression is associated with poor survival in breast cancer. Br. J. Cancer 100, 1055-1060 (2009
100. Nimeus-Malmstrom, E. et al. Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort. Int. J. Cancer 127, 961-967 (2010
101. Tassan, J. P., Jaquenoud, M., Leopold, P., Schultz, S. J., & Nigg, E. A. Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C. Proc. Natl Acad. Sci. USA 92, 8871-8875 (1995
102. Akoulitchev, S., Chuikov, S., & Reinberg, D. TFIIH is negatively regulated by CDK8-containing mediator complexes. Nature 407, 102-106 (2000
103. Spangler, L., Wang, X., Conaway, J. W., Conaway, R. C., & Dvir, A. TFIIH action in transcription initiation and promoter escape requires distinct regions of downstream promoter DNA. Proc. Natl Acad. Sci. USA 98, 5544-5549 (2001
104. Ye, X., Zhu, C., & Harper, J. W. A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. Proc. Natl Acad. Sci. USA 98, 1682-1686 (2001
105. Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173-11178 (1996
106. Pozo, K. et al. The role of CDK5 in neuroendocrine thyroid cancer. Cancer Cell 24, 499-511 (2013
107. Whittaker, S. R., Walton, M. I., Garrett, M. D., & Workman, P. The Cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-Activated protein kinase pathway. Cancer Res. 64, 262-272 (2004
108. Shapiro, G. I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770-1783 (2006
109. Sedlacek, H. et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. 9, 1143-1168 (1996
110. Bose, P., S. G. L., & Grant, S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin. Investig. Drugs. 22, 723-738 (2013
111. Lin, T. S. et al. Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders. J. Clin. Oncol. 28, 418-423 (2010
112. Kouroukis, C. T. et al. Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 21, 1740-1745 (2003
113. Byrd, J. C. et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood. 109, 399-404 (2007)
114. Lapenna, S. Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nature Rev. Drug Discov. 8, 547-566 (2009
115. Blum, K. A. et al. Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. Leukemia 25, 1444-1451 (2011
116. Le Tourneau, C. et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur. J. Cancer 46, 3243-3250 (2010
117. Payton, M. et al. Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer Res. 66, 4299-4308 (2006
118. Parry, D. et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther. 9, 2344-2353 (2010
119. DePinto, W. et al. In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in Phase I clinical trials. Mol. Cancer Ther. 5, 2644-2658 (2006
120. Misra, R. N. et al. N-(cycloalkylamino)acyl-2-Aminothiazole inhibitors of cyclin-dependent kinase N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J. Med. Chem. 47, 1719-1728 (2004
121. Nemunaitis, J. J. et al. A first-in-human, Phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J. Transl. Med. 11, 259 (2013
122. Mita, M. M. et al. Randomized Phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin. Breast Cancer 14, 169-176 (2014
123. Stephenson, J. J. et al. Randomized Phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer. Lung Cancer 83, 219-223 (2014
124. Gojo, I. et al. Phase II study of the cyclin-dependent kinase (CDK) inhibitor dinaciclib (SCH 727965) in patients with advanced acute leukemias. ASH Annual Meeting Abstracts 116, 3287 (2010
125. Kumar, S. K. et al. Phase 1/2 trial of a novel CDK inhibitor dinaciclib (SCH727965) in patients with relapsed multiple myeloma demonstrates encouraging single agent activity. ASH Annual Meeting Abstracts 120, 76 (2012
126. Blachly, J. S., & Byrd, J. C. Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk. Lymphoma 54, 2133-2143 (2013
127. Raje, N. et al. A Phase I/II open-label multicenter study of the cyclin kinase inhibitor AT7519M alone and in combination with bortezomib in patients with previously treated multiple myeloma (ASH 55th meeting abstract). Blood 122, 1976 (2013
128. Diab, S. et al. A Phase I study of R547, a novel, selective inhibitor of cell cycle and transcriptional cyclin dependent kinases (CDKs). J. Clin. Oncol. 25, 3528 (2007
129. Tong, W. G. et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J. Clin. Oncol. 28, 3015-3022 (2010
130. Heath, E. I., B. K., Martell, R. E., Adelman, D. C., & Lorusso, P. M. A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors. Invest. New Drugs. 26, 59-65 (2008
131. Byth, K. F. et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol. Cancer Ther. 8, 1856-1866 (2009
132. Boss, D. S. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. Ann. Oncol. 21, 884-894 (2010
133. Mahoney, E., Byrd, J. C., & Johnson, A. J. Autophagy and ER stress play an essential role in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Autophagy 9, 434-435 (2013
134. Carlson, B. A., Dubay, M. M., Sausville, E. A., Brizuela, L., & Worland, P. J. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 56, 2973-2978 (1996
135. Kelland, L. R. Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. Expert Opin. Investig. Drugs 9, 2903-2911 (2000
136. Senderowicz, A. M. et al. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J. Clin. Oncol. 16, 2986-2999 (1998
137. Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108-112 (2009
138. Kang, J., Sergio, C. M., Sutherland, R. L., & Musgrove, E. A. Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells. BMC Cancer 14, 32 (2014
139. Huang, C. H. et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 28, 1800-1814 (2014
140. Johnson, N. et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nature Med. 17, 875-882 (2011
141. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates ?-catenin activity. Nature 455, 547-551 (2008
142. Kwiatkowski, N. et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616-620 (2014
143. Walsby, E. et al. A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget 5, 375-385 (2014
144. Kozar, K., & Sicinski, P. Cell cycle progression without cyclin D-CDK4 and cyclin D-CDK6 complexes. Cell Cycle 4, 388-391 (2005
145. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477-491 (2004
146. Yu, Q., Geng, Y., & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017-1021 (2001
147. Choi, Y. J. et al. The requirement for cyclin D function in tumor maintenance. Cancer Cell 22, 438-451 (2012
148. Sawai, C. M. et al. Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. Cancer Cell 22, 452-465 (2012
149. VanderWel, S. N. et al. Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase J. Med. Chem. 48, 2371-2387 (2005
150. Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427-1438 (2004
151. Toogood, P. L. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem. 48, 2388-2406 (2005
152. Dean, J. L., Thangavel, C., McClendon, A. K., Reed, C. A., & Knudsen, E. S. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29, 4018-4032 (2010
153. Rivadeneira, D. B. et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 138, 1920-1930 (2010
154. Dean, J. L. et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 11, 2756-2761 (2012
155. Finn, R. S. 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. Breast Cancer Res. 11, R77 (2009
156. Michaud, K. et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 70, 3228-3238 (2010
157. Rader, J. et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 19, 6173-6182 (2013
158. Dickson, M. A. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res. 20, 3379-3383 (2014
159. Zhang, Y. X. et al. Antiproliferative effects of CDK4/6 inhibition in CDK4-Amplified human liposarcoma in vitro and in vivo. Mol. Cancer Ther. 13, 2184-2193 (2014
160. Vora, S. R. et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26, 136-149 (2014
161. Gelbert, L. M. et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest. New Drugs 32, 825-837 (2014
162. Tate, S. C. et al. Semi-mechanistic pharmacokinetic/Pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin. Cancer Res. 20, 3763-3774 (2014
163. Schwartz, G. K. et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br. J. Cancer 104, 1862-1868 (2011
164. Vaughn, D. et al. Treatment of growing teratoma syndrome. N. Engl J. Med. 360, 423-424 (2009
165. Leonard, J. P. et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119, 4597-4607 (2012
166. Dickson, M. A. et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-Amplified well-differentiated or dedifferentiated liposarcoma. J. Clin. Oncol 31, 2024-2028 (2013
167. Infante, J. R. et al. A Phase I study of the single-Agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. J. Clin. Oncol. 32 (Suppl.), 2528 (2014
168. Shapiro, G. et al. A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J. Clin. Oncol. 31 (Suppl.), 2500, (2013
169. Miller, T. W. et al. ER?-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1, 338-351 (2011
170. Thangavel, C. et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer 18, 333-345 (2011). References 155, 169 and 170 provide much of the evidence that CDK4 and CDK6 inhibitors would be efficacious in ER-positive breast cancer.
171. Desmedt, C., & Sotiriou, C. Proliferation: the most prominent predictor of clinical outcome in breast cancer. Cell Cycle 5, 2198-2202 (2006
172. Finn, R. S. et al. S1-6 Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2-Advanced breast cancer (BC). Cancer Res. 72 (Suppl. 24) (2012
173. Finn, R. S. et al. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2-Advanced breast cancer (PALOMA-1; TRIO-18). Cancer Res. 74, CT101 (2014
174. Finn, R. S. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 16, 25-35 (2015
175. Konecny, G. E. et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin. Cancer Res. 17, 1591-1602 (2011
176. Logan, J. E. et al. PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res. 33, 2997-3004 (2013
177. Carozzi, F. et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol. 9, 937-945 (2008
178. Flaherty, K. T. et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin. Cancer Res. 18, 568-576 (2012
179. Roberts, P. J. et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J. Natl Cancer Inst. 104, 476-487 (2012
180. McClendon, A. K. et al. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 11, 2747-2755 (2012
181. Dean, J. L., McClendon, A. K., & Knudsen, E. S. Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem. 287, 29075-29087 (2012
182. Witkiewicz, A. K., Cox, D., & Knudsen, E. S. CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer 5, 261-272 (2014
183. Kwong, L. N. et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nature Med. 18, 1503-1510 (2012
184. Heilmann, A. M. et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 74, 3947-3958 (2014
185. Franco, J., Witkiewicz, A. K., & Knudsen, E. S. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget 5, 6512-6525 (2014
186. [No authors listed.] Drug combo shows promise in NRAS-mutant melanoma. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-NB2014-098 (2014). References 160 and 181-185 demonstrate the important cooperative mechanisms between CDK4 and CDK6 and targeted therapies in multiple cancers.
187. Marzec, M. et al. Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity. Blood 108, 1744-1750 (2006
188. Menu, E. et al. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res. 68, 5519-5523 (2008
189. Puyol, M. et al. A synthetic lethal interaction between K-RAS oncogenes and CDK4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63-73 (2010
190. Comstock, C. E. et al. Targeting cell cycle and hormone receptor pathways in cancer. Oncogene 32, 5481-5491 (2013
191. Barton, K. L. et al. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS ONE 8, e77639 (2013
192. Wiedemeyer, W. R. et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc. Natl Acad. Sci. USA 107, 11501-11506 (2010
193. Young, R. J. et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell. Melanoma Res. 27, 590-600 (2014
194. Yadav, V. et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol. Cancer Ther. 13, 2253-2263 (2014
195. Whiteway, S. L. et al. Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells. J. Neurooncol 111, 113-121 (2013
196. Ismail, A. et al. Early G1 cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma. Clin. Cancer Res. 17, 4513-4522 (2011
197. Liu, F., & Korc, M. Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol. Cancer Ther. 11, 2138-2148 (2012
198. Slamon, D. J. et al. Phase I study of PD 0332991, cyclin-D kinase (CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of patients with ER-positive, HER2-negative breast cancer. J Clin Oncol Abstr. 28:15s, 3060 (2010
199. DeMichele, A. et al. A Phase II trial of an oral CDK 4/6 inhibitor, D0332991, in advanced breast cancer. J. Clin Oncol Abstr. 31, 519 (2013
200. Bardia, A. et al. Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women with ER+/HER2-metastatic breast cancer. J. Clin. Oncol. 32 (Suppl.), 535 (2014
201. Munster, P. et al. Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2? BC). J. Clin Oncol. 32 (Suppl.), 533 (2014
202. Sosman, J. et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity. J. Clin. Oncol. 32 (Suppl.), 9009 (2014
203. Goldman, J.W. et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer. J. Clin. Oncol. 32 (Suppl.), 8026 (2014
204. Patnaik, A. et al. LY2825219, a novel cell cycle inhibitor for CDK4/6, in combination with fulvestrant for patients with hromone receptor positive (HR+ve) metastatic breast cancer. J. Clin Oncol. 32 (Suppl.), 524 (2014).