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Review
. 2014 Aug 4:6:123-33.
doi: 10.2147/BCTT.S46725. eCollection 2014.

Palbociclib: an evidence-based review of its potential in the treatment of breast cancer

Karen A Cadoo  1 , Ayca Gucalp  1 , Tiffany A Traina  1
Affiliations
Review

Palbociclib: an evidence-based review of its potential in the treatment of breast cancer

Karen A Cadoo et al. Breast Cancer (Dove Med Press). .

Abstract

Cellular proliferation, growth, and division following DNA (deoxyribonucleic acid) damage are tightly controlled by the cell-cycle regulatory machinery. This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress. The cell-cycle regulatory process plays a critical role in oncogenesis and in the development of therapeutic resistance; it is frequently disrupted in breast cancer, providing a rational target for therapeutic development. Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models. Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer. In this article we review the cell cycle and its regulatory processes, their role in breast cancer, and the rationale for CDK inhibition in this disease. We describe the preclinical and clinical data relating to the activity of palbociclib in breast cancer and the plans for the future development of this agent.

Keywords: CDK4/6 inhibition; cell-cycle regulation; cyclin-dependent kinases.

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Figures

Figure 1
Figure 1
The cell cycle and regulatory process. Notes: Cell division and the cell cycle are tightly controlled by a number of positive and negative regulators. Mitogenic signals upregulate and activate cyclin D, resulting in the complexing of cyclin D with CDK4 or -6. These complexes facilitate the addition of phosphate groups (P) to RB leading ultimately to the release of bound E2F transcription factors and allowing the cell to divide. The CDKs and their cyclin partners are positive regulators of the cell cycle, while RB, other tumor suppressors (p16INK4, p15INK4b, p18INK4c, and p19INK4d), and the CDK-interacting protein/kinase inhibitory protein (Cip/Kip) family negatively regulate. Abbreviations: AR, androgen receptor; CDK, cyclin-dependent kinase; ER, estrogen receptor; NF-κB, nuclear factor κB; PR, progesterone receptor; RB, retinoblastoma; R, restriction point; P, phosphate.
Figure 2
Figure 2
Palbociclib, or PD-0332991, a CDK4/6 inhibitor from Pfizer, Inc. (New York, NY, USA).
Figure 3
Figure 3
Inhibitory concentration and cell type. Notes: Bar graph of IC50 values (nM) and cell type. Cell lines are color coded by subtype: light blue, luminal; dark blue bars or stripes, HER2 amplified; yellow, non-luminal/undergone an epithelial-to-mesenchymal transition; red, non-luminal; and turquoise, immortalized. Reproduced from 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. 2009;11(5):R77. Abbreviation: IC50, half maximal inhibitory concentration.
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