Advertisement

Targeting Breast Cancer with CDK Inhibitors

  • Erica L. MayerEmail author
Breast Cancer (B Overmoyer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Breast Cancer

Abstract

Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Re-establishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy. Three oral agents selectively targeting CDK4/6 have been developed: palbociclib, abemaciclib, and LEE011. Preclinical models show optimal activity in hormone receptor positive breast cancer, which may display biologic features suggesting particular dependence on the CDK4/cyclin D1/Rb interaction. Palbociclib has been studied in a randomized phase 2 clinical trial in metastatic hormone receptor positive breast cancer in which the combination of palbociclib and endocrine therapy significantly prolonged progression-free survival over endocrine therapy alone. The toxicity profile of palbociclib and the other CDK 4/6 inhibitors in early phase I and II trials has been predominantly hematologic, characterized by limited neutropenia, as well as variable gastrointestinal toxicity. Multiple phase II and III studies are ongoing with all three agents, and are designed to explore the role of CDK 4/6 inhibition in metastatic hormone receptor positive breast cancer. The next wave of studies will examine further clinical and scientific topics, including the role of CDK 4/6 inhibition in the neo/adjuvant setting, the combination of CDK 4/6 inhibitors with other targeted therapies, and the activity of CDK 4/6 inhibitors in the HER2 positive subset of breast cancer, as well as in other cancer subtypes. Should ongoing study confirm benefits and tolerability of CDK 4/6 inhibition, combination therapy with endocrine agents may become a new standard of care for hormone receptor positive breast cancer.

Keywords

Breast cancer Hormone-receptor positive Cell cycle CDK inhibition Palbociclib Abemaciclib LEE011 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Erica L. Mayer has received compensation from Pfizer for service as a consultant.

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.

References

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

  1. 1.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  2. 2.
    Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res. 2014;20:3379–83.CrossRefPubMedGoogle Scholar
  3. 3.
    Cadoo KA, Gucalp A, Traina TA. Palbociclib: an evidence-based review of its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press). 2014;6:123–33.PubMedCentralGoogle Scholar
  4. 4.
    Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002;2:103–12.CrossRefPubMedGoogle Scholar
  5. 5.
    Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993;8:2127–33.PubMedGoogle Scholar
  6. 6.
    Hui R, Macmillan RD, Kenny FS, et al. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res. 2000;6:2777–87.PubMedGoogle Scholar
  7. 7.•
    Finn RS, Dering J, Conklin D, 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: BCR. 2009;11:R77. Preclinical evidence supports preferential activity of palbociclib in luminal (hormone receptor positive) subtype breast cancer, as well as describes synergistic interactions when palbociclib is combined with tamoxifen and trastuzumab.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Watts CK, Brady A, Sarcevic B, et al. Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol. 1995;9:1804–13.PubMedGoogle Scholar
  9. 9.
    Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocrine-Related Cancer. 2011;18:333–45.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Zwijsen RM, Wientjens E, Klompmaker R, et al. CDK-independent activation of estrogen receptor by cyclin D1. Cell. 1997;88:405–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Shapiro GI. Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin Cancer Res. 2004;10:4270s–5s.CrossRefPubMedGoogle Scholar
  12. 12.
    Bose P, Simmons GL, Grant S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin Investig Drugs. 2013;22:723–38.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Criscitiello C, Viale G, Esposito A, et al. Dinaciclib for the treatment of breast cancer. Expert Opin Investig Drugs. 2014;23:1305–12.CrossRefPubMedGoogle Scholar
  14. 14.
    Konecny GE, Winterhoff B, Kolarova T, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2011;17:1591–602.CrossRefGoogle Scholar
  15. 15.
    Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3:1427–38.PubMedGoogle Scholar
  16. 16.
    Cen L, Carlson BL, Schroeder MA, et al. p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro-Oncology. 2012;14:870–81.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012;119:4597–607.CrossRefPubMedGoogle Scholar
  18. 18.
    Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 2011;104:1862–8.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    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:Off J Am Assoc Cancer Res. 2012;18:568–76.CrossRefGoogle Scholar
  20. 20.
    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;15s:A3060.Google Scholar
  21. 21.
    Clark AS, O'Dwyer PJ, Heitjan D, et al. A phase I trial of palbociclib and paclitaxel in metastatic breast cancer. ASCO Meeting Abstracts. 2014;5s:A527.Google Scholar
  22. 22.
    McClendon AK, Dean JL, Rivadeneira DB, et al. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle. 2012;11:2747–55.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    DeMichele A, Clark A, Tan KS, et al. CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb + Advanced Breast Cancer: Phase II Activity, Safety and Predictive Biomarker Assessment. Clin Cancer Res. 2014.Google Scholar
  24. 24.••
    Finn RS, Crown JP, Lang I, 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. 2014. The PALOMA 1 randomized phase 2 trial established the activity of the CDK 4/6 inhibitor palbociclib, described the toxicity profile in metastatic disease, and suggested superiority over standard first-line therapy with aromatase inhibitor.Google Scholar
  25. 25.
    Gelbert LM, Cai S, Lin X, 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. 2014;32:825–37.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Tate SC, Cai S, Ajamie RT, 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. 2014;20:3763–74.CrossRefPubMedGoogle Scholar
  27. 27.•
    Sanchez-Martinez C, Gelbert L, Shannon H, et al. 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. 2011;10:B234. Abemaciclib, a CDK 4/6 inhibitor, has a differentiated activity and tolerability profile in comparison to palbociclib, and in particular, the potential ability to cross the blood brain barrier.CrossRefGoogle Scholar
  28. 28.
    Patnaik A, Rosen L, Tolaney S, et al. LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer. J Clin Oncol. 2014;325s:A534.Google Scholar
  29. 29.
    Infante JR, Shapiro G, Witteveen P, 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. 2014;5s:A2528.Google Scholar
  30. 30.••
    Vora SR, Juric D, Kim N, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26:136–49. A complex relationship exists between PI3 kinase, Rb, and CDK 4/6. This preclinical experience suggests the combination of targeted biologics: a PI3K inhibitor and a CDK 4/6 inhibitor, is active and can overcome aspects of tumor resistance to therapy.CrossRefPubMedGoogle Scholar
  31. 31.
    O'Brien N, Di Tomaso E, Ayala R, et al. In vivo efficacy of combined targeting of CDK4/6, ER and PI3K signaling in ER+ breast cancer Proceedings AACR:A4756 2014.Google Scholar
  32. 32.
    Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19:5320–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Susan F Smith Center for Women’s Cancers, Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA

Personalised recommendations