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

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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.

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Most cited references 33

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Targeting the cell cycle: a new approach to cancer therapy.

Gary K. Schwartz, Manish A. Shah (2005)

The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.

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CDK-independent activation of estrogen receptor by cyclin D1.

R. Klompmaker, R Zwijsen, J T Eijk … (1997)

Both cyclin D1 and estrogens have an essential role in regulating proliferation of breast epithelial cells. We show here a novel role for cyclin D1 in growth regulation of estrogen-responsive tissues by potentiating transcription of estrogen receptor-regulated genes. Cyclin D1 mediates this activation independent of complex formation to a CDK partner. Cyclin D1 activates estrogen receptor-mediated transcription in the absence of estrogen and enhances transcription in its presence. The activation of estrogen receptor by cyclin D1 is not inhibited by anti-estrogens. A direct physical binding of cyclin D1 to the hormone binding domain of the estrogen receptor results in an increased binding of the receptor to estrogen response element sequences, and upregulates estrogen receptor-mediated transcription. These results highlight a novel role for cyclin D1 as a CDK-independent activator of the estrogen receptor.

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ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.

Ketty Gonzalez, Siprachanh Chanthaphaychith, Michael R. Miller … (2011)

Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER(+) xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers. ©2011 AACR.

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Author and article information

Journal

Journal ID (nlm-ta): Breast Cancer (Dove Med Press)

Journal ID (iso-abbrev): Breast Cancer (Dove Med Press)

Journal ID (publisher-id): Breast Cancer: Targets and Therapy

Title: Breast Cancer : Targets and Therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1179-1314

Publication date Collection: 2014

Publication date (Electronic): 04 August 2014

Volume: 6

Pages: 123-133

Affiliations

Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA

Author notes

Correspondence: Tiffany A Traina, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, Evelyn H Lauder Breast Center, 300 East 66th Street, New York, NY 10065, USA, Tel +1 646 888 4558, Fax +1 646 888 4917

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Publisher ID: bctt-6-123

DOI: 10.2147/BCTT.S46725

PMC ID: 4128689

PubMed ID: 25177151

SO-VID: 4d49adc5-87ce-40e8-bdd8-56c8c3265074

License:

The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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

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Cancer Metabolism

Most cited references 33

Targeting the cell cycle: a new approach to cancer therapy.

CDK-independent activation of estrogen receptor by cyclin D1.

ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.

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