Treating cancer with selective CDK4/6 inhibitors

Key Points

  • The actions of cyclin-dependent kinases (CDK) 4/6, through phosphorylation of retinoblastoma-associated protein 1 (RB1) are pivotal in the transition from G1 to S phase in many cancer cells

  • The effectiveness of non-selective inhibition of CDKs is hampered by toxicities, selective CDK4/6 inhibition results in fewer toxicities and also provides promising antitumour effectiveness in various tumour types

  • Evidence of antitumour activity from phase III trials is currently available for palbociclib in patients with hormone-receptor (HR) positive metastatic breast cancer that have progressed on prior endocrine therapy

  • CDK4/6 inhibitors are most effective in combination with endocrine therapy in patients with HR-positive breast cancer: preclinical data support the combination of CDK4/6 inhibitors with PI3K and/or MAPK inhibitors

  • Loss of RB1 function is an established mechanism of primary resistance to CDK4/6 inhibitors in vitro, but this, and other biomarkers are yet to be validated clinically

Abstract

Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.

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Figure 1: Classical and non-classical models of the cell cycle in RB1-proficient cells.
Figure 2: Chemical structure of selective CDK4/6 inhibitors.
Figure 3: The cell cycle and the role of CDK4/6 inhibition.
Figure 4: Possible combination therapies CDK4/6 inhibitors.

References

  1. 1

    Hartwell, L. H., Culotti, J., Pringle, J. R. & Reid, B. J. Genetic control of the cell division cycle in yeast. Science 183, 46–51 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    CAS  PubMed  Google Scholar 

  3. 3

    Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009).

    CAS  Google Scholar 

  4. 4

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

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Asghar, U., Witkiewicz, A. K., Turner, N. C. & Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 14, 130–146 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    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).

    CAS  PubMed  Google Scholar 

  7. 7

    Shapiro, G. et al. A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer [abstract]. J. Clin. Oncol. 31 (Suppl.), a2500 (2013).

    Google Scholar 

  8. 8

    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 [abstract]. J. Clin. Oncol. 32 (Suppl.), 8026 (2014).

    Google Scholar 

  9. 9

    Patnaik, A. et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer [abstract]. Cancer Res. CT232 (2014).

  10. 10

    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  PubMed Central  Google Scholar 

  11. 11

    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 

  12. 12

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    DeMichele, A. et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin. Cancer Res. 21, 995–1001 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    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 [abstract]. J. Clin. Oncol. 32 (Suppl.), 2528 (2014).

    Google Scholar 

  15. 15

    Sosman, J. A. et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity [abstract]. J. Clin. Oncol. 32 (Suppl.), 9009 (2014).

    Google Scholar 

  16. 16

    Munster, P. N. et al. Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2− BC) [abstract]. J. Clin. Oncol. 32 (Suppl.), 533 (2014).

    Google Scholar 

  17. 17

    Juric, D. et al. Abstract P5-19-24: phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2− breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res. 75, P5-19-24 (2015).

    Google Scholar 

  18. 18

    Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Cristofanilli, M. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(15)00613-0

  20. 20

    Hartwell, L. H. Saccharomyces cerevisiae cell cycle. Bacteriol. Rev. 38, 164 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Dorée, M. & Hunt, T. From Cdc2 to Cdk1: when did the cell cycle kinase join its cyclin partner? J. Cell Sci. 115, 2461–2464 (2002).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D. & Hunt, T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33, 389–396 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Pines, J. & Hunter, T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature 346, 760–763 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Tsai, L.-H., Harlow, E. & Meyerson, M. Isolation of the human cdk2 gene that encodes the cyclin A and adenovirus E1A-associated p33 kinase. Nature 353, 174–177 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Blagosklonny, M. V. & Pardee, A. B. The restriction point of the cell cycle. Cell Cycle 1, 102–109 (2002).

    Google Scholar 

  27. 27

    Lew, D. J., Dulic´, V. & Reed, S. I. Isolation of three novel human cyclins by rescue of G1 cyclin (cln) function in yeast. Cell 66, 1197–1206 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    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  PubMed Central  Google Scholar 

  29. 29

    Xiong, Y., Connolly, T., Futcher, B. & Beach, D. Human D-type cyclin. Cell 65, 691–699 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Baldin, V., Lukas, J., Marcote, M. J., Pagano, M. & Draetta, G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7, 812–821 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Aktas, H., Cai, H. & Cooper, G. M. Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol. Cell. Biol. 17, 3850–3857 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Peeper, D. S. et al. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature 386, 177–181 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Matsushime, H. et al. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71, 323–334 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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, 331–331 (1993).

    CAS  PubMed  Google Scholar 

  36. 36

    Meyerson, M. & Harlow, E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol. Cell. Biol. 14, 2077–2086 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Weintraub, S. J., Prater, C. A. & Dean, D. C. Retinoblastoma protein switches the E2F site from positive to negative element. Nature 358, 259–261 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Hiebert, S. W., Chellappan, S. P., Horowitz, J. M. & Nevins, J. R. The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes Dev. 6, 177–185 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Sellers, W. R., Rodgers, J. W. & Kaelin, W. G. Jr. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Proc. Natl Acad. Sci. USA 92, 11544–11548 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Weintraub, S. J. et al. Mechanism of active transcriptional repression by the retinoblastoma protein. Nature 375, 812–816 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Goodrich, D. W., Wang, N. P., Qian, Y.-W., Lee, E. Y.-H. P. & Lee, W.-H. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell 67, 293–302 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Harbour, J. W., Luo, R. X., Santi, A. D., Postigo, A. A. & Dean, D. C. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98, 859–869 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Pagano, M., Draetta, G. & Jansen-Durr, P. Association of cdk2 kinase with the transcription factor E2F during S phase. Science 255, 1144–1147 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Devoto, S. H., Mudryj, M., Pines, J., Hunter, T. & Nevins, J. R. A cyclin A–protein kinase complex possesses sequence-specific DNA binding activity: 33cdk2 is a component of the E2F–cyclin A complex. Cell 68, 167–176 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Lees, E., Faha, B., Dulic, V., Reed, S. & Harlow, E. Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes Dev. 6, 1874–1885 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    DeCaprio, J. A. et al. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell 58, 1085–1095 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Chen, P.-L., Scully, P., Shew, J.-Y., Wang, J. Y. J. & Lee, W.-H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58, 1193–1198 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Buchkovich, K., Duffy, L. A. & Harlow, E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58, 1097–1105 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Classon, M. & Harlow, E. The retinoblastoma tumour suppressor in development and cancer. Nat. Rev. Cancer 2, 910–917 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Zhang, H. S. et al. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101, 79–89 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Luo, R. X., Postigo, A. A. & Dean, D. C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    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  PubMed Central  Google Scholar 

  53. 53

    Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371, 257–261 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Hirai, H., Roussel, M. F., Kato, J., Ashmun, R. A. & Sherr, C. J. Novel INK4 proteins, 19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol. Cell. Biol. 15, 2672–2681 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Chan, F., Zhang, J., Cheng, L., Shapiro, D. N. & Winoto, A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol. Cell. Biol. 15, 2682–2688 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Zhang, H. S., Postigo, A. A. & Dean, D. C. Active transcriptional repression by the Rb–E2F complex mediates G1 arrest triggered by p16INK4a, TGFβ, and contact inhibition. Cell 97, 53–61 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Wieser, R. J., Faust, D., Dietrich, C. & Oesch, F. p16INK4 mediates contact-inhibition of growth. Oncogene 18, 277–281 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Okamoto, A. et al. Mutations and altered expression of p16INK4 in human cancer. Proc. Natl Acad. Sci. USA 91, 11045–11049 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Shapiro, G. I. et al. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell Lines. Cancer Res. 55, 505–509 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Kratzke, R. A. et al. Rb and p16INK4a expression in resected non-small cell lung tumors. Cancer Res. 56, 3415–3420 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Benedict, W. F. et al. Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene 18, 1197–1203 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Zerfass-Thome, K. et al. p27KIP1 blocks cyclin E-dependent transactivation of cyclin A gene expression. Mol. Cell. Biol. 17, 407–415 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Wade Harper, J., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816 (1993).

    Google Scholar 

  65. 65

    Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    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 

  67. 67

    Lee, M. H., Reynisdóttir, I. & Massagué, J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 9, 639–649 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Matsuoka, S. et al. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 9, 650–662 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Lamphere, L. et al. Interaction between Cdc37 and Cdk4 in human cells. Oncogene 14, 1999–2004 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Zhao, Q., Boschelli, F., Caplan, A. J. & Arndt, K. T. Identification of a conserved sequence motif that promotes Cdc37 and cyclin D1 binding to Cdk4. J. Biol. Chem. 279, 12560–12564 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10, 1491–1502 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Medema, R. H., Herrera, R. E., Lam, F. & Weinberg, R. A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc. Natl Acad. Sci. USA 92, 6289–6293 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Harper, J. W. et al. Inhibition of cyclin-dependent kinases by p21. Mol. Biol. Cell 6, 387–400 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Blain, S. W., Montalvo, E. & Massagué, J. Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A–Cdk2 and cyclin D2–Cdk4. J. Biol. Chem. 272, 25863–25872 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    McConnell, B. B., Gregory, F. J., Stott, F. J., Hara, E. & Peters, G. Induced expression of p16INK4a inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin–CDK–inhibitor complexes. Mol. Cell. Biol. 19, 1981–1989 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Parry, D., Mahony, D., Wills, K. & Lees, E. Cyclin D–CDK subunit arrangement is dependent on the availability of competing INK4 and p21 class inhibitors. Mol. Cell. Biol. 19, 1775–1783 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–8862 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Rane, S. G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat. Genet. 22, 44–52 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Tsutsui, T. et al. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27Kip1 activity. Mol. Cell. Biol. 19, 7011–7019 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Martin, J. et al. Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number. Oncogene 22, 5261–5269 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504 (2004).

    CAS  PubMed  Google Scholar 

  82. 82

    Spencer, S. L. et al. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155, 369–383 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Tetsu, O. & McCormick, F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3, 233–245 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

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

    CAS  PubMed  Google Scholar 

  85. 85

    Xiong, Y., Zhang, H. & Beach, D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71, 505–514 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Ren, S. & Rollins, B. J. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 117, 239–251 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Rochette-Egly, C., Adam, S., Rossignol, M., Egly, J.-M. & Chambon, P. Stimulation of RARα activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. Cell 90, 97–107 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Tirode, F., Busso, D., Coin, F. & Egly, J.-M. Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. Mol. Cell 3, 87–95 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Wallenfang, M. R. & Seydoux, G. cdk-7 is required for mRNA transcription and cell cycle progression in Caenorhabditis elegans embryos. Proc. Natl Acad. Sci. USA 99, 5527–5532 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    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 

  91. 91

    Nguyen, V. T., Kiss, T., Michels, A. A. & Bensaude, O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414, 322–325 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Yang, Z., Zhu, Q., Luo, K. & Zhou, Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414, 317–322 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Rathkopf, D. et al. Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors. Clin. Cancer Res. 15, 7405–7411 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Byrd, J. C. et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B Study 19805. Clin. Cancer Res. 11, 4176–4181 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    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 (2006).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Schwartz, G. K. et al. Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J. Clin. Oncol. 20, 2157–2170 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Luke, J. J. et al. The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Clin. Cancer Res. 18, 2638–2647 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Shah, M. A. et al. A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol. Clin. Cancer Res. 11, 3836–3845 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Benson, C. et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br. J. Cancer 96, 29–37 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    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  PubMed Central  Google Scholar 

  101. 101

    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 

  102. 102

    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 

  103. 103

    Erikson, J., Finan, J., Tsujimoto, Y., Nowell, P. C. & Croce, C. M. The chromosome 14 breakpoint in neoplastic B cells with the t(11;14) translocation involves the immunoglobulin heavy chain locus. Proc. Natl Acad. Sci. USA 81, 4144–4148 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Bosch, F. et al. PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma. Blood 84, 2726–2732 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Rosenberg, C. L. et al. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc. Natl Acad. Sci. USA 88, 9638–9542 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Tsujimoto, Y. et al. Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 224, 1403–1406 (1984).

    CAS  PubMed  Google Scholar 

  107. 107

    Akervall, J. A. et al. Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 79, 380–389 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Michalides, R. et al. Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res. 55, 975–978 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Jares, P. et al. PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas. Cancer Res. 54, 4813–4817 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Bova, R. J. et al. Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the anterior tongue. Clin. Cancer Res. 5, 2810–2819 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Gillett, C. et al. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res. 54, 1812–1817 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Weinstat-Saslow, D. et al. Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat. Med. 1, 1257–1260 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Kenny, F. S. et al. Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin. Cancer Res. 5, 2069–2076 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    McIntosh, G. G. et al. Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 11, 885–891 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Yu, Q. et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Betticher, D. C. et al. Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br. J. Cancer 73, 294 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Gautschi, O., Ratschiller, D., Gugger, M., Betticher, D. C. & Heighway, J. Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. Lung Cancer 55, 1–14 (2007).

    PubMed  PubMed Central  Google Scholar 

  118. 118

    Jiang, W. et al. Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc. Natl Acad. Sci. USA 90, 9026–9030 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

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

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Smalley, K. S. et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol. Cancer Ther. 7, 2876–2883 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Chraybi, M. et al. Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations. Hum. Pathol. 44, 1902–1911 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Brennan, Cameron, W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl Acad. Sci. USA 110, 4009–4014 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Barretina, J. et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat. Genet. 42, 715–721 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Italiano, A. et al. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. Int. J. Cancer 122, 2233–2241 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Italiano, A. et al. Clinical and biological significance of CDK4 amplification in well-differentiated and dedifferentiated liposarcomas. Clin. Cancer Res. 15, 5696–5703 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Cen, L. et al. p16–Cdk4–Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro Oncol. 14, 870–881 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    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  PubMed Central  Google Scholar 

  130. 130

    Baba, Y. et al. LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma. Clin. Cancer Res. 20, 1114–1124 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Parker, E. P. K. et al. Sequencing of t(2;7) translocations reveals a consistent breakpoint linking CDK6 to the IGK locus in indolent B-cell neoplasia. J. Mol. Diagn. 15, 101–109 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Parker, E., MacDonald, J. R. & Wang, C. Molecular characterization of a t(2;7) translocation linking CDK6 to the IGK locus in CD5 monoclonal B-cell lymphocytosis. Cancer Genet. 204, 260–264 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Douet-Guilbert, N. et al. Translocation t(2;7)(p11;q21) associated with the CDK6/IGK rearrangement is a rare but recurrent abnormality in B-cell lymphoproliferative malignancies. Cancer Genet. 207, 83–86 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Olanich, M. E. et al. CDK4 amplification reduces sensitivity to CDK4/6 inhibition in fusion-positive rhabdomyosarcoma. Clin. Cancer Res. 21, 4947–4959 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Zuo, L. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat. Genet. 12, 97–99 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    FitzGerald, M. G. et al. Prevalence of germ-line mutations in p16, 19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population. Proc. Natl Acad. Sci. USA 93, 8541–8545 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Soufir, N. et al. Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, 14ARF or cdk4 genes. Br. J. Cancer 82, 818–822 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Cairns, P. et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat. Genet. 11, 210–212 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Caldas, C. et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 8, 27–32 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Hussussian, C. J. et al. Germline p16 mutations in familial melanoma. Nat. Genet. 8, 15–21 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Finn, R. 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 

  143. 143

    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 

  144. 144

    Musgrove, E. A. & Caldon, C. E. Barraclough, J., Stone, A. & Sutherland, R. L. Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11, 558–572 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Sørlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

    PubMed  PubMed Central  Google Scholar 

  146. 146

    The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  147. 147

    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 

  148. 148

    Bosco, E. E. & Knudsen, E. S. RB in breast cancer: the crossroads of tumorigenesis and treatment. Cell Cycle 6, 667–671 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Ertel, A. et al. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9, 4153–4163 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Herschkowitz, J. I., He, X., Fan, C. & Perou, C. M. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 10, R75 (2008).

    PubMed  PubMed Central  Google Scholar 

  151. 151

    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, 1488–11499 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Mariaule, G. & Belmont, P. Cyclin-dependent kinase inhibitors as marketed anticancer drugs: where are we now? A short survey. Molecules 19, 14366–14382 (2014).

    PubMed  PubMed Central  Google Scholar 

  153. 153

    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  PubMed Central  Google Scholar 

  154. 154

    Gelbert, L. 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 

  155. 155

    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  PubMed Central  Google Scholar 

  156. 156

    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 

  157. 157

    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 

  158. 158

    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 

  159. 159

    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  PubMed Central  Google Scholar 

  160. 160

    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  PubMed Central  Google Scholar 

  161. 161

    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  PubMed Central  Google Scholar 

  162. 162

    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  PubMed Central  Google Scholar 

  163. 163

    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  PubMed Central  Google Scholar 

  164. 164

    Baughn, L. B. et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res. 66, 7661–7667 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    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  PubMed Central  Google Scholar 

  166. 166

    Wang, L. et al. Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood 110, 2075–2083 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    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 

  168. 168

    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, 1920–11930 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Lee, R. J. et al. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol. Cell. Biol. 20, 672–683 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Herrera-Abreu, M. T. et al. PI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis. Ann. Oncol. 26 (Suppl. 3), iii29–iii30 (2015).

    Google Scholar 

  172. 172

    Thangavel, C. et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer 18, 333–345 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Kim, S. et al. Abstract PR02: LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6 — reactivating Rb in cancer. Mol. Cancer Ther. 12, R02 (2013).

    Google Scholar 

  174. 174

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

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Schultz, K. A. P., Petronio, J., Bendel, A., Patterson, R. & Vaughn, D. J. PD0332991 (palbociclib) for treatment of pediatric intracranial growing teratoma syndrome. Pediatr. Blood Cancer 62, 1072–1074 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Vaughn, D. J. et al. Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors. Cancer 121, 1463–1468 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    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, 2024–2048 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Tolaney, S. M. et al. Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer [abstract]. Cancer Res. P5-19-13 (2015).

  179. 179

    Parrish, K. E. et al. Abstract C81: BBB efflux pump activity limits brain penetration of palbociclib (PD0332991) in glioblastoma. Mol. Cancer Ther. 12, C81 (2013).

    Google Scholar 

  180. 180

    Sanchez-Martinez, C. et al. Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood–brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts. Mol. Cancer Ther. 10, B234–B234 (2011).

    Google Scholar 

  181. 181

    Tripathy, D. et al. Phase III, randomized, double-blind, placebo-controlled study of ribociclib (LEE011) in combination with either tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of premenopausal women with HR+, HER2− advanced breast cancer (aBC): MONALEESA-7 [abstract]. J. Clin. Oncol. 33 (Suppl.), TPS625 (2015).

    Google Scholar 

  182. 182

    Goldman, J. W. et al. Treatment rationale and study design for the JUNIPER study: a randomized phase III study of abemaciclib with best supportive care versus erlotinib with best supportive care in patients with stage IV non-small-cell lung cancer with a detectable KRAS mutation whose disease has progressed after platinum-based chemotherapy. Clin. Lung Cancer 17, 80–84 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Llombart, A. et al. A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2) [abstract]. Cancer Res. 75, OT1-1-07 (2015).

    Google Scholar 

  184. 184

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  185. 185

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  186. 186

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  187. 187

    U.S. Food and Drug administration. Palbociclib. [online], (2015).

  188. 188

    Leo, A. D. et al. Final overall survival: fulvestrant 500mg versus 250mg in the randomized CONFIRM trial. J. Natl Cancer Inst. 106, 1–7 (2014).

    Google Scholar 

  189. 189

    Abukhdeir, A. M. et al. Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc. Natl Acad. Sci. USA 105, 288–293 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Vora, Sadhna, 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 

  191. 191

    Toy, W. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45, 1439–1445 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Robinson, D. R. et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45, 1446–1451 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Wardell, S. E. et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy resistant breast cancer. Clin. Cancer Res. 21, 5121–5130 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Yu, Q. et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Niesvizky, R. et al. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk. Lymphoma 56, 3320–3328 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Chiron, D. et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 4, 1022–1035 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Chiron, D. et al. Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1. Cell Cycle 12, 1892–1900 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

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

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Ziemke, E. K. et al. Sensitivity of KRAS-mutant colorectal cancers to combination therapy that co-targets MEK and CDK4/6. Clin. Cancer Res. 22, 405–414 (2015).

    PubMed  PubMed Central  Google Scholar 

  200. 200

    Olson, M. F., Paterson, H. F. & Marshall, C. J. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394, 295–299 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Mao, C. Q. et al. Synthetic lethal therapy for KRAS mutant non-small-cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery. Mol. Ther. 22, 964–973 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    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  PubMed Central  Google Scholar 

  203. 203

    Bardia, A. et al. Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women with ER+/HER2-metastatic breast cancer [abstract]. J. Clin. Oncol. 32 (Suppl.), 535 (2014).

    Google Scholar 

  204. 204

    Li, C. et al. AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia. Mol. Cancer Ther. 14, 375–383 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    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 

  206. 206

    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 

  207. 207

    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 

  208. 208

    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 

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Acknowledgements

We acknowledge funding from the UK NHS to the Royal Marsden NIHR Biomedical Research Centre.

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All authors made a substantial contribution to researching data for this article, discussions of content, writing the manuscript, and reviewing and/or editing of the manuscript prior to submission.

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Correspondence to Nicholas C. Turner.

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N.C.T. is a member of the advisory boards of Lilly, Novartis and Pfizer. R.S.F. declares that he has acted as an advisor for Bayer Pharmaceuticals, Bristol–Myers Squibb, Novartis, and Pfizer, and has received research support from these companies via his institution. B.O. declares no competing interests.

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O'Leary, B., Finn, R. & Turner, N. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13, 417–430 (2016). https://doi.org/10.1038/nrclinonc.2016.26

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