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

Cadoo KA, Gucalp A, Traina TA - Breast Cancer (Dove Med Press) (2014)

Bottom Line: This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress.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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus

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.
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f1-bctt-6-123: 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.

Mentions: The addition of targeted agents to our armamentarium has provided the potential for significant clinical benefit for patients with metastatic breast cancer (MBC).1 Extensive efforts are underway to design novel therapies, including those that target vulnerabilities within the cancer cell cycle. Aberrations of the cell cycle are ubiquitous in cancer,2 and there is increasing recognition of the role of cell-cycle regulators in intrinsic and acquired resistance to therapy.3 Cellular proliferation and growth, in addition to division following deoxyribonucleic acid (DNA) damage, are tightly controlled by the cell-cycle regulatory machinery. Cell-cycle transition and the commitment to cell division are coordinated by cyclin-dependent protein kinases (CDKs) (Figure 1). These serine/threonine kinases rely on a regulatory cyclin partner to form CDK–cyclin heterodimer complexes that control cell cycling.2 Palbociclib is a potent and selective inhibitor of CDK4 and -6, which are critical components of the cell-cycle regulatory machinery. This review will discuss the role of the cell cycle in breast cancer and the data relating to palbociclib as a therapeutic strategy.


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

Cadoo KA, Gucalp A, Traina TA - Breast Cancer (Dove Med Press) (2014)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128689&req=5

f1-bctt-6-123: 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.
Mentions: The addition of targeted agents to our armamentarium has provided the potential for significant clinical benefit for patients with metastatic breast cancer (MBC).1 Extensive efforts are underway to design novel therapies, including those that target vulnerabilities within the cancer cell cycle. Aberrations of the cell cycle are ubiquitous in cancer,2 and there is increasing recognition of the role of cell-cycle regulators in intrinsic and acquired resistance to therapy.3 Cellular proliferation and growth, in addition to division following deoxyribonucleic acid (DNA) damage, are tightly controlled by the cell-cycle regulatory machinery. Cell-cycle transition and the commitment to cell division are coordinated by cyclin-dependent protein kinases (CDKs) (Figure 1). These serine/threonine kinases rely on a regulatory cyclin partner to form CDK–cyclin heterodimer complexes that control cell cycling.2 Palbociclib is a potent and selective inhibitor of CDK4 and -6, which are critical components of the cell-cycle regulatory machinery. This review will discuss the role of the cell cycle in breast cancer and the data relating to palbociclib as a therapeutic strategy.

Bottom Line: This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress.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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus