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Cyclin Kinase Inhibitors in Breast Cancer: From Bench to Bedside

  • Systemic Therapy (J Cortes, Section Editor)
  • Published:
Current Breast Cancer Reports Aims and scope Submit manuscript

Abstract

A precise knowledge of cell-cycle machinery and its effect on tumorigenesis has led to the development of a large number of anticancer drugs targeting this pathway. In breast cancer research, the promising results of recent clinical trials of novel selective CDK-inhibitors, for example palbociclib, have generated high expectations for this field. This review gathers the results of the most recent clinical trials of CDK inhibitors for breast cancer, and outlines their potential as anticancer therapy.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Jemal A, Siegel R, Xu J, Ward E, Cancer statistics. CA Cancer J Clin. 2010;60(5):277–300.

    Article  PubMed  Google Scholar 

  2. Harris CA, Ward RL, Dobbins TA, Drew AK, Pearson S. The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis. Ann Oncol. 2011;22(6):1308–17.

    Article  CAS  PubMed  Google Scholar 

  3. Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev. 2009;4:CD003370.

    PubMed  Google Scholar 

  4. Robert A. Weinberg The biology of cancer. second ed. Garland Sciences; 2014.

  5. DeVita, Hellman, Rosenberg. Cancer, principles and practice of Oncology. ninth ed. Lippincott Williams & Wilkins; 2011.

  6. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153–66. This manuscript reviews cell cycle functioning and components and their relevance in normal and cancer tissue, providing background for a better understanding of new approaches in targeted therapies, for example CDK inhibitors.

    Article  CAS  PubMed  Google Scholar 

  7. Cooper G, Hausman R. The cell: a molecular approach. 5th ed. Washington: ASM Press;.

  8. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem. 2006;97(2):261–74.

    Article  CAS  PubMed  Google Scholar 

  9. Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J Clin Oncol. 2005;23(18):4215–24.

    Article  CAS  PubMed  Google Scholar 

  10. Santarius T, Shipley J, Brewer D, Stratton MR, Cooper CS. A census of amplified and overexpressed human cancer genes. Nat Rev Cancer. 2010;10(1):59–64.

    Article  CAS  PubMed  Google Scholar 

  11. Musgrove EA, Caldon CE, Barraclough J, Stone A. Sutherland RL Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11(8):558–72. This review outlines the oncogenic effect and common dysregulation of cyclin D in tumorogenesis, focusing in breast cancer, through both CDK dependent and independent pathways.

    Article  CAS  PubMed  Google Scholar 

  12. Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene. 2006;25(11):1620–8.

    Article  CAS  PubMed  Google Scholar 

  13. Millar EK, Dean JL, McNeil CM, O'Toole SA, Henshall SM, Tran T, et al. Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome. Oncogene. 2009;28(15):1812–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. An HX, Beckmann MW, Reifenberger G, Bender HG, Niederacher D. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol. 1999;154(1):113–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Yu Q, Sicinska E, Geng Y, Ahnström M, Zagozdzon A, Kong Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006;9(1):23–32.

    Article  CAS  PubMed  Google Scholar 

  16. Oesterreich S, Fuqua SA. Tumor suppressor genes in breast cancer. Endocr Relat Cancer. 1999;6(3):405–19.

    Article  CAS  PubMed  Google Scholar 

  17. Bosco EE, Knudsen ES. RB in breast cancer: at the crossroads of tumorigenesis and treatment. Cell Cycle. 2007;6(6):667–71.

    Article  CAS  PubMed  Google Scholar 

  18. Bosco EE, Wang Y, Xu H, Zilfou JT, Knudsen KE, Aronow BJ, et al. The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J Clin Invest. 2007;117(1):218–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, et al. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle. 2010;9(20):4153–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumor suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10(5):R75.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Jiang Z, Jones R, Liu JC, Deng T, Robinson T, Chung PE, et al. RB1 and p53 at the crossroad of EMT and triple-negative breast cancer. Cell Cycle. 2011;10(10):1563–70. This article reviews the connection between Rb, p53, and epithelial-to mesenchymal transition in triple negative breast cancer (TNBC) and underlines the need for a better understanding of this circuit in the search for novel targeted therapies for TNBC.

    Article  CAS  PubMed  Google Scholar 

  22. Moore JD. In the wrong place at the wrong time: does cyclin mislocalization drive oncogenic transformation. Nat Rev Cancer. 2013;13(3):201–8. doi:10.1038/nrc3468. This article emphasizes the potential use of ex-vivo tumor explant culture approaches to determine the sensitivity of the primary tumor to a therapeutic agent. It specifically studies the correlation between the Rb pathway and the response to PD-0332991.

    Article  CAS  PubMed  Google Scholar 

  23. Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Res. 2004;6(1):13–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Chiarle R, Pagano M, Inghirami G. The cyclin dependent kinase inhibitor p27 and its prognostic role in breast cancer. Breast Cancer Res. 2001;3(2):91–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Flaherty KT, LoRusso PM, DeMichele A, 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. 2011;18:568–76.

    Article  PubMed  Google Scholar 

  26. Pfizer, Data on File, 2013.

  27. Slamon DJ, Hurvitz SA, Applebaum S, 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. 2010;28:15s. suppl; abstr 3060.

    Google Scholar 

  28. Finn RS, Crown JP, Lang I, et al. results of a randomized Phase 2 Study of PD 0332991, a Cyclin-Dependant Kinase (CDK) 4/6 Inhibitor, in combination with Letrozol vs Letrozol Alone for First-Line Treatment of ER+/Her2- Advanced Breast Cancer (BC). Cancer Res. 2012;72(24 Suppl):S1–6. Encouraging results of an interim analysis of this randomized phase 2 trial comapring letrozole alone vs combination with palbociclib for First-Line Treatment of ER+/Her2- Advanced Breast Cancer was present at the 2012 San Antonio breast Cancer Symposium.

  29. Infante JR, Shapiro GI, Witteveen PO, et al. Phase I Multicenter, Open-label, Dose-escalation Study of LEE011, an Oral Inhibitor of Cyclin-dependent Kinase 4/6, in Patients with Advanced Solid Tumors or Lymphomas. AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther 2013; 19–23.

  30. Joshi KS, Rathos MJ, Mahajan P, et al. p 276–00, a nocel cyclin-dependent inhibitor, induces G1–G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther. 2007;6:926–34.

    Article  CAS  PubMed  Google Scholar 

  31. Parry D, Guzi T, Shanahan F, et al. Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor. Mol Cancer Ther. 2010;9:2344–53.

    Article  CAS  PubMed  Google Scholar 

  32. Neumunaitis JJ, Small KA, Kirschmeier P, et al. A first-in-human, phase I, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11:259.

    Article  Google Scholar 

  33. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclinD kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R7. This study identifies the correlation between genes associated with luminal type, retinoblastoma pathway and response to PD 0332991, resulting in the blockage of Rb phosphorylation.

    Article  Google Scholar 

  34. CDK Inhibitor Triples PFS in Breast Cancer. Cancer Discov. 2013;3:4. Published OnlineFirst December 13, 2012.

  35. Altucci L, Addeo R, Cicatiello L, Dauvois S, Parker MG, Truss M, et al. 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogenesis. 1996;12(11):2315–24.

    CAS  Google Scholar 

  36. Foster JS, Wimalasena J. Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells. Mol Endocrinol. 1996;10(5):488–98.

    CAS  PubMed  Google Scholar 

  37. Prall OW, Sarcevic B, Musgrove EA, Watts CK. Sutherland RL Estrogen-induced activation of Cdk4 and Cdk2 during G1 S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem. 1997;272(16):10882–94.

    Article  CAS  PubMed  Google Scholar 

  38. Hui R, Cornish AL, McClelland RA, Robertson JF, Blamey RW, Musgrove EA, et al. Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Cancer Res. 1996;2(6):923–8.

    CAS  PubMed  Google Scholar 

  39. Jiang Z, Deng T, Jones R, Li H, Herschkowitz JI, Liu JC, et al. Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending onp53 status. J Clin Invest. 2010;120(9):3296–309.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle. 2012;11(14):2756–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst. 2012;104(6):476–87. This review focuses on the spatial deregulation of cyclin expression and its potential link to oncogenesis.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res. 2011;17(6):1591–602.

    Article  CAS  PubMed  Google Scholar 

  43. Wiedemeyer WR, Dunn IF, Quayle SN, Zhang J, Chheda MG, Dunn GP, et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci U S A. 2010;107(25):11501–6.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM, Creasman KJ, Bazarov AV, Smyth JW, Davis SE, Yaswen P, Mills GB, Esserman LJ, Goga A. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition.

  45. Nanos-Webb A, Jabbour NA, Multani AS, Wingate H, Oumata N, Galons H, et al. Targeting low molecular weight cyclin E (LMW-E) in breast cancer. Breast Cancer Res Treat. 2012;132(2):575–88.

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

Gabriela Torres, Isabel Echavarría, Miriam Lobo, Ivan Márquez-Rodas, and Miguel Martin have nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Dr Esquerdo 46, 28007, Madrid, Spain

    Gabriela Torres, Isabel Echavarría, Miriam Lobo, Ivan Márquez-Rodas & Miguel Martin

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  1. Gabriela Torres
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Correspondence to Miguel Martin.

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Torres, G., Echavarría, I., Lobo, M. et al. Cyclin Kinase Inhibitors in Breast Cancer: From Bench to Bedside. Curr Breast Cancer Rep 6, 79–87 (2014). https://doi.org/10.1007/s12609-014-0142-3

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  • DOI: https://doi.org/10.1007/s12609-014-0142-3

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