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Overcoming Endocrine Resistance in Hormone-Receptor Positive Advanced Breast Cancer-The Emerging Role of CDK4/6 Inhibitors.

O'Sullivan CC - Int J Cancer Clin Res (2015)

Bottom Line: By using various different mechanisms, malignant cells may increase cyclin D-dependent activity.The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in breast cancer; making it a rational target for anticancer therapy.To date, three oral highly selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are in various stages of clinical development: PD0332991 (palbociclib), LEE011 (ribociclib) and LY2835219 (abemaciclib).

View Article: PubMed Central - HTML - PubMed

Affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.

ABSTRACT

Dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may inhibit senescence and promote cellular proliferation. By using various different mechanisms, malignant cells may increase cyclin D-dependent activity. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in breast cancer; making it a rational target for anticancer therapy. To date, three oral highly selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are in various stages of clinical development: PD0332991 (palbociclib), LEE011 (ribociclib) and LY2835219 (abemaciclib). Results from phase I, II and III trials in hormone-receptor (HR)-positive breast cancer have been encouraging, demonstrating convincing efficacy and a tolerable side-effect profile (mainly uncomplicated neutropenia). This article will review the preclinical and clinical development of the CDK4/6i, as well as reviewing the existing preclinical evidence regarding combination of these agents with chemotherapy and other targeted therapies. Future and ongoing clinical trials, which may expand the potential application of these agents, will also be discussed. In summary, CDK4/6i are exciting compounds which may change the therapeutic landscape of HR-positive breast cancer.

No MeSH data available.


Related in: MedlinePlus

The role of Cyclin D, CDK4/6 and Rb in cell cycle progression.PI3K/Akt: phosphotidylinositol kinase/Akt, MAPK: mitogen-activated protein kinases, CDK4/6: cyclin-dependent kinase 4/6, NFκB: Nuclear Factor-Kappa B, ER: estrogen receptor, PR: progesterone receptor, AR: androgen receptor, RB: retinoblastoma, P: phosphate.
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Figure 1: The role of Cyclin D, CDK4/6 and Rb in cell cycle progression.PI3K/Akt: phosphotidylinositol kinase/Akt, MAPK: mitogen-activated protein kinases, CDK4/6: cyclin-dependent kinase 4/6, NFκB: Nuclear Factor-Kappa B, ER: estrogen receptor, PR: progesterone receptor, AR: androgen receptor, RB: retinoblastoma, P: phosphate.

Mentions: Imbalance between cellular senescence and proliferation is a classic feature of cancer [11,12]. When cells reach the “restriction point” during the G1 phase of the cell cycle, they decide whether or not to progress to S-phase, or rest in G0 phase [13]; a decision which is influenced by antigrowth signals. The cell cycle machinery mediates anti-proliferative signals from the extracellular environment by promoting transition from the G1 phase to the S phase [14]. These signals are then transmitted via the retinoblastoma tumor suppression protein (Rb), and related proteins p107 and p130. Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases, which interact with specific regulatory subunits called cyclins [15]. In order for cells to transition from G1 to S phase, Rb must be phosphorylated by CDK4 or CDK6 (often called CDK4/6 as they have similar mechanisms of action [16], and their activating cyclins (D1, D2 or D3) [17] (Figure 1). The CDK interacting protein/ kinase inhibitory protein (Cip/Kip) family also regulates formation of activated cyclin D-CDK4/6 heterodimers [18]. Phosphorylation and inactivation of Rb causes dissociation of E2F transcription factors and transcriptional regulation of genes which play an important role in facilitating G1-S phase transition, DNA replication, DNA repair and mitosis [19–24]. The cyclin-D/CDK4/6-Rb pathway, therefore, plays a key role in cell cycle regulation as it is downstream of multiple mitogenic cascades, making it an important target for drug development [25]. For example, treatment of endocrine-resistant breast cancer cell lines with the highly selective CDK 4/6 inhibitor palbociclib resulted in dephosphorylation of Rb and cell-cycle arrest, which was not seen when the cell lines were treated with fulvestrant [26]. This is particularly relevant given that there are many mechanisms of endocrine resistance, although not all of these are directly related to the cell cycle [27–31].


Overcoming Endocrine Resistance in Hormone-Receptor Positive Advanced Breast Cancer-The Emerging Role of CDK4/6 Inhibitors.

O'Sullivan CC - Int J Cancer Clin Res (2015)

The role of Cyclin D, CDK4/6 and Rb in cell cycle progression.PI3K/Akt: phosphotidylinositol kinase/Akt, MAPK: mitogen-activated protein kinases, CDK4/6: cyclin-dependent kinase 4/6, NFκB: Nuclear Factor-Kappa B, ER: estrogen receptor, PR: progesterone receptor, AR: androgen receptor, RB: retinoblastoma, P: phosphate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697745&req=5

Figure 1: The role of Cyclin D, CDK4/6 and Rb in cell cycle progression.PI3K/Akt: phosphotidylinositol kinase/Akt, MAPK: mitogen-activated protein kinases, CDK4/6: cyclin-dependent kinase 4/6, NFκB: Nuclear Factor-Kappa B, ER: estrogen receptor, PR: progesterone receptor, AR: androgen receptor, RB: retinoblastoma, P: phosphate.
Mentions: Imbalance between cellular senescence and proliferation is a classic feature of cancer [11,12]. When cells reach the “restriction point” during the G1 phase of the cell cycle, they decide whether or not to progress to S-phase, or rest in G0 phase [13]; a decision which is influenced by antigrowth signals. The cell cycle machinery mediates anti-proliferative signals from the extracellular environment by promoting transition from the G1 phase to the S phase [14]. These signals are then transmitted via the retinoblastoma tumor suppression protein (Rb), and related proteins p107 and p130. Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases, which interact with specific regulatory subunits called cyclins [15]. In order for cells to transition from G1 to S phase, Rb must be phosphorylated by CDK4 or CDK6 (often called CDK4/6 as they have similar mechanisms of action [16], and their activating cyclins (D1, D2 or D3) [17] (Figure 1). The CDK interacting protein/ kinase inhibitory protein (Cip/Kip) family also regulates formation of activated cyclin D-CDK4/6 heterodimers [18]. Phosphorylation and inactivation of Rb causes dissociation of E2F transcription factors and transcriptional regulation of genes which play an important role in facilitating G1-S phase transition, DNA replication, DNA repair and mitosis [19–24]. The cyclin-D/CDK4/6-Rb pathway, therefore, plays a key role in cell cycle regulation as it is downstream of multiple mitogenic cascades, making it an important target for drug development [25]. For example, treatment of endocrine-resistant breast cancer cell lines with the highly selective CDK 4/6 inhibitor palbociclib resulted in dephosphorylation of Rb and cell-cycle arrest, which was not seen when the cell lines were treated with fulvestrant [26]. This is particularly relevant given that there are many mechanisms of endocrine resistance, although not all of these are directly related to the cell cycle [27–31].

Bottom Line: By using various different mechanisms, malignant cells may increase cyclin D-dependent activity.The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in breast cancer; making it a rational target for anticancer therapy.To date, three oral highly selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are in various stages of clinical development: PD0332991 (palbociclib), LEE011 (ribociclib) and LY2835219 (abemaciclib).

View Article: PubMed Central - HTML - PubMed

Affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.

ABSTRACT

Dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may inhibit senescence and promote cellular proliferation. By using various different mechanisms, malignant cells may increase cyclin D-dependent activity. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in breast cancer; making it a rational target for anticancer therapy. To date, three oral highly selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are in various stages of clinical development: PD0332991 (palbociclib), LEE011 (ribociclib) and LY2835219 (abemaciclib). Results from phase I, II and III trials in hormone-receptor (HR)-positive breast cancer have been encouraging, demonstrating convincing efficacy and a tolerable side-effect profile (mainly uncomplicated neutropenia). This article will review the preclinical and clinical development of the CDK4/6i, as well as reviewing the existing preclinical evidence regarding combination of these agents with chemotherapy and other targeted therapies. Future and ongoing clinical trials, which may expand the potential application of these agents, will also be discussed. In summary, CDK4/6i are exciting compounds which may change the therapeutic landscape of HR-positive breast cancer.

No MeSH data available.


Related in: MedlinePlus