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

Key Points

  • Cyclin-dependant kinase 4 (CDK4) and CDK6 phosphorylate the tumour suppressor retinoblastoma protein (RB), resulting in the release of the E2F transcription factor and progression through the cell cycle. CDK4 and CDK6 are positively regulated by D-type cyclins (that is, cyclin D1, cyclin D2 and cyclin D3) and negatively regulated by inhibitor of CDK4 (INK4) proteins.

  • In cancer, the CDK4/CDK6–RB–p16INK4A pathway is dysregulated through various mechanisms, including loss of p16INK4A, loss of RB, overexpression of cyclin D1 or of CDK4 and CDK6.

  • Clinical trials with pan-CDK inhibitors, such as flavopiridol, have demonstrated low levels of clinical activity and drug target selectivity. The reasons for their failure in the clinic include the absence of clear biomarkers for response and the lack of a clear therapeutic window.

  • The selective CDK4 and CDK6 inhibitors palbociclib, LEE011 and abemaciclib induce G1 cell cycle arrest both in vitro and in vivo in RB-proficient models. Preclinical activity has been reported in multiple tumour types, including breast cancer, sarcoma, melanoma and mantle cell lymphoma.

  • The PALOMA-1 Phase II clinical trial randomized 165 women with advanced oestrogen receptor (ER)-positive breast cancer into two treatment groups: the aromatase inhibitor letrozole alone versus letrozole plus palbociclib. There was a significant improvement of 10 months in median progression-free survival with letrozole plus palbociclib compared with letrozole alone

  • Neutropaenia is the principal drug-limiting toxicity for the selective CDK4 and CDK6 inhibitors palbociclib and LEE011. Abemaciclib has demonstrated more prominent gastrointestinal-associated toxicity.

  • Loss of RB and higher levels of p16INK4A are markers of resistance to selective CDK4 and CDK6 inhibitors. Further evaluation of predictive biomarkers across tumour types is required.

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.

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Figure 1: Progression of the cell cycle driven by CDKs.
Figure 2: G1–S regulatory modules and relevance to cancer.
Figure 3: Summary of the biological functions of CDK complexes.
Figure 4: Deregulation of CDK regulatory genes in cancer.
Figure 5: Selected CDK inhibitors.

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References

  1. Nurse, P., Masui, Y. & Hartwell, L. Understanding the cell cycle. Nature Med. 4, 1103–1106 (1998).

    CAS  PubMed  Google Scholar 

  2. Sherr, C. J. Cancer cell cycles. Science 274, 1672–1677 (1996).

    CAS  PubMed  Google Scholar 

  3. Lim, S. & Kaldis, P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 140, 3079–3093 (2013).

    CAS  PubMed  Google Scholar 

  4. Malumbres, M. Therapeutic opportunities to control tumor cell cycles. Clin. Transl. Oncol. 8, 399–408 (2006).

    CAS  PubMed  Google Scholar 

  5. Hunt, T., Nasmyth, K. & Novak, B. The cell cycle. Phil. Trans. R. Soc. B 366, 3494–3497 (2011).

    PubMed  PubMed Central  Google Scholar 

  6. Hunt, T. Nobel Lecture. Protein synthesis, proteolysis, and cell cycle transitions. Biosci. Rep. 22, 465–486 (2002).

    CAS  PubMed  Google Scholar 

  7. Nurse, P. M. Nobel Lecture. Cyclin dependent kinases and cell cycle control. Biosci. Rep. 22, 487–499 (2002).

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bregman, D. B., Pestell, R. G. & Kidd, V. J. Cell cycle regulation and RNA polymerase II. Front. Biosci. 5, D244–D257 (2000).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  12. Malumbres, M. & Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nature Rev. Cancer 1, 222–231 (2001).

    CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  15. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504 (2004). This is one of multiple papers demonstrating that selective CDK activities can be bypassed by compensatory pathways and the underlying plasticity within the cell cycle.

    CAS  PubMed  Google Scholar 

  16. Hu, M. G. et al. A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res. 69, 810–818 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sherr, C. J. D-type cyclins. Trends Biochem. Sci. 20, 187–190 (1995).

    CAS  PubMed  Google Scholar 

  18. Diehl, J. A. Cycling to cancer with cyclin D1. Cancer Biol. Ther. 1, 226–231 (2002).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  21. Sicinski, P. et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384, 470–474 (1996).

    CAS  PubMed  Google Scholar 

  22. Kushner, J. A. et al. Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth. Mol. Cell. Biol. 25, 3752–3762 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  24. Cooper, A. B. et al. A unique function for cyclin D3 in early B cell development. Nature Immunol. 7, 489–497 (2006).

    CAS  Google Scholar 

  25. Ciemerych, M. A. et al. Development of mice expressing a single D-type cyclin. Genes Dev. 16, 3277–3289 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  27. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  33. Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001).

    CAS  PubMed  Google Scholar 

  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). This study provides a key link between the induction of p16INK4A and the blockade of oncogene-driven tumorigenesis.

    CAS  PubMed  Google Scholar 

  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-β. Genes Dev. 9, 1831–1845 (1995).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  40. Matsushime, H. et al. D-type cyclin-dependent kinase activity in mammalian cells. Mol. Cell. Biol. 14, 2066–2076 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, J. Y., Knudsen, E. S. & Welch, P. J. The retinoblastoma tumor suppressor protein. Adv. Cancer Res. 64, 25–85 (1994).

    CAS  PubMed  Google Scholar 

  42. Burkhart, D. L. & Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Rev. Cancer 8, 671–682 (2008).

    CAS  Google Scholar 

  43. Knudsen, E. S. & Knudsen, K. E. Tailoring to RB: tumour suppressor status and therapeutic response. Nature Rev. Cancer 8, 714–724 (2008).

    CAS  Google Scholar 

  44. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  45. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    CAS  PubMed  Google Scholar 

  46. Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell 152, 340–351 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. LaPak, K. M. & Burd, C. E. The molecular balancing act of p16INK4a in cancer and aging. Mol. Cancer Res. 12, 167–183 (2014).

    CAS  PubMed  Google Scholar 

  48. Lukas, J. et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503–506 (1995).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Motokura, T. et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350, 512–515 (1991).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  52. Jiang, W. et al. Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res. 52, 2980–2983 (1992).

    CAS  PubMed  Google Scholar 

  53. Buckley, M. F. et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 8, 2127–2133 (1993).

    CAS  PubMed  Google Scholar 

  54. Bartkova, J. et al. Cyclin D1 protein expression and function in human breast cancer. Int. J. Cancer 57, 353–361 (1994).

    CAS  PubMed  Google Scholar 

  55. Khatib, Z. A. et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 53, 5535–5541 (1993).

    CAS  PubMed  Google Scholar 

  56. Park, S. et al. Aberrant CDK4 amplification in refractory rhabdomyosarcoma as identified by genomic profiling. Sci. Rep. 4, 3623 (2014).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Okuda, M. et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103, 127–140 (2000).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  64. Moroy, T. & Geisen, C. Cyclin, E. Int. J. Biochem. Cell Biol. 36, 1424–1439 (2004).

    CAS  PubMed  Google Scholar 

  65. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints. Genes Dev. 16, 245–256 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Sherr, C. J. Cell cycle control and cancer. Harvey Lect. 96, 73–92 (2000).

    PubMed  Google Scholar 

  67. Bartek, J., Bartkova, J. & Lukas, J. The retinoblastoma protein pathway in cell cycle control and cancer. Exp. Cell Res. 237, 1–6 (1997).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  69. el-Deiry, W. S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

    CAS  PubMed  Google Scholar 

  70. Polyak, K. et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev. 8, 9–22 (1994).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  72. van den Heuvel, S. & Harlow, E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262, 2050–2054 (1993).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Etemadmoghadam, D. et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc. Natl Acad. Sci. USA 110, 19489–19494 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  79. Lukas, J. et al. Cyclin E-induced S phase without activation of the pRB/E2F pathway. Genes Dev. 11, 1479–1492 (1997).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hershko, D. D. Cyclin-dependent kinase inhibitor p27 as a prognostic biomarker and potential cancer therapeutic target. Future Oncol. 6, 1837–1847 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sadasivam, S. & DeCaprio, J. A. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nature Rev. Cancer 13, 585–595 (2013).

    CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gavet, O. & Pines, J. Progressive activation of CyclinB1–Cdk1 coordinates entry to mitosis. Dev. Cell 18, 533–543 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Nigg, E. A. Polo-like kinases: positive regulators of cell division from start to finish. Curr. Opin. Cell Biol. 10, 776–783 (1998).

    CAS  PubMed  Google Scholar 

  91. Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448, 811–815 (2007).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  93. Nigg, E. A. Mitotic kinases as regulators of cell division and its checkpoints. Nature Rev. Mol. Cell Biol. 2, 21–32 (2001).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  95. Bharadwaj, R. & Yu, H. The spindle checkpoint, aneuploidy, and cancer. Oncogene 23, 2016–2027 (2004).

    CAS  PubMed  Google Scholar 

  96. Morgan, D. O. Regulation of the APC and the exit from mitosis. Nature Cell Biol. 1, E47–E53 (1999).

    CAS  PubMed  Google Scholar 

  97. Taylor, W. R. & Stark, G. R. Regulation of the G2/M transition by p53. Oncogene 20, 1803–1815 (2001).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  99. Aaltonen, K. et al. High cyclin B1 expression is associated with poor survival in breast cancer. Br. J. Cancer 100, 1055–1060 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Akoulitchev, S., Chuikov, S. & Reinberg, D. TFIIH is negatively regulated by CDK8-containing mediator complexes. Nature 407, 102–106 (2000). This seminal study defines the role of selected CDK family members in transcriptional regulation.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Pozo, K. et al. The role of CDK5 in neuroendocrine thyroid cancer. Cancer Cell 24, 499–511 (2013). This important study defines a role for CDK5 in driving tumour initiation and progression and as a potential therapeutic target in cancer.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  108. Shapiro, G. I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770–1783 (2006).

    CAS  PubMed  Google Scholar 

  109. Sedlacek, H. et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. 9, 1143–1168 (1996).

    CAS  PubMed  Google Scholar 

  110. Bose, P., S. G. L. & Grant, S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin. Investig. Drugs. 22, 723–738 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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)

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Lapenna, S. Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nature Rev. Drug Discov. 8, 547–566 (2009).

    CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  117. Payton, M. et al. Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer Res. 66, 4299–4308 (2006).

    CAS  PubMed  Google Scholar 

  118. Parry, D. et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther. 9, 2344–2353 (2010). This study illustrates the potency of the multiple-CDK inhibitor dinaciclib in preclinical models.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  120. Misra, R. N. et al. N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. 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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  126. Blachly, J. S. & Byrd, J. C. Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk. Lymphoma 54, 2133–2143 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  137. Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  139. Huang, C. H. et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 28, 1800–1814 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Johnson, N. et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nature Med. 17, 875–882 (2011).

    CAS  PubMed  Google Scholar 

  141. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455, 547–551 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Kwiatkowski, N. et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616–620 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Walsby, E. et al. A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget 5, 375–385 (2014).

    PubMed  Google Scholar 

  144. Kozar, K. & Sicinski, P. Cell cycle progression without cyclin D–CDK4 and cyclin D–CDK6 complexes. Cell Cycle 4, 388–391 (2005).

    CAS  PubMed  Google Scholar 

  145. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004).

    CAS  PubMed  Google Scholar 

  146. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001). This seminal study illustrates the tumour context-specific requirement for cyclin D1.

    CAS  PubMed  Google Scholar 

  147. Choi, Y. J. et al. The requirement for cyclin D function in tumor maintenance. Cancer Cell 22, 438–451 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. VanderWel, S. N. et al. Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4. J. Med. Chem. 48, 2371–2387 (2005).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Rader, J. et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 19, 6173–6182 (2013).

    CAS  PubMed  Google Scholar 

  158. Dickson, M. A. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res. 20, 3379–3383 (2014).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  160. Vora, S. R. et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26, 136–149 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Vaughn, D. et al. Treatment of growing teratoma syndrome. N. Engl J. Med. 360, 423–424 (2009).

    CAS  PubMed  Google Scholar 

  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). This Phase II study provides proof of concept that selective CDK4 and CDK6 inhibitors can have clinical activity in selected tumours.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  169. Miller, T. W. et al. ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1, 338–351 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Desmedt, C. & Sotiriou, C. Proliferation: the most prominent predictor of clinical outcome in breast cancer. Cell Cycle 5, 2198–2202 (2006).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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). This paper presents the clinical data that now support multiple Phase III studies of CDK4 and CDK6 inhibition in concert with hormone therapy.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. McClendon, A. K. et al. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 11, 2747–2755 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Kwong, L. N. et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nature Med. 18, 1503–1510 (2012).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  190. Comstock, C. E. et al. Targeting cell cycle and hormone receptor pathways in cancer. Oncogene 32, 5481–5491 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

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Acknowledgements

The authors thank their colleagues in the field for guidance, critical discussion and editorial advice related to the preparation of this manuscript. They also regret any omissions. N.C.T. acknowledges funding from the UK National Health Service to the Royal Marsden and the Institute of Cancer Research NIHR Biomedical Research Centre. E.S.K. acknowledges research funding from the US National Institutes of Health/National Cancer Institute (NIH/NCI) (CA129134 and CA188650). A.K.W. acknowledges research funding from the NIH/NCI (CA163863).

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A.K.W. has received honoraria from Pfizer and Permeon. N.C.T. has received honoraria from Pfizer and Novartis, and research funding from Pfizer and Roche. E.S.K. has received honoraria from Eli Lilly and Pfizer, and research funding from Pfizer. U.A. declares no competing interests.

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Asghar, U., Witkiewicz, A., Turner, N. et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14, 130–146 (2015). https://doi.org/10.1038/nrd4504

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