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The Role of CDK4/6
in Breast Cancer
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Presentation Overview
● Brief overview of breast cancer
● Role of cyclin-dependent kinases 4 and 6 (CDK4/6)
in normal and tumor cells
● Role of CDK4/6 in estrogen receptor-positive (ER+)
breast cancer
3
Brief Overview of
Breast Cancer
Breast Cancer Epidemiology (United States)
● Breast cancer is one of the most common cancers
affecting women in the United States, with a lifetime
risk of 1 in 8 (12%)1
● Nearly 30% of women diagnosed with early breast
cancer will eventually progress to advanced disease2
● It is estimated that 250,000 women in the United
States are living with advanced breast cancer3
● Exceeded only by lung cancer, breast cancer is the
second leading cause of cancer death in women1
● 39,620: the estimated number of US women who
died from breast cancer in 20131
1. American Cancer Society. www.cancer.org/acs/groups/cid/documents/webcontent/003090-pdf.pdf. Accessed December 16, 2013;
2. O’Shaughnessy J. Oncologist. 2005;10(suppl 3):20-29; 3. AdvancedBC.org. www.advancedbc.org/node/26. Accessed December 9, 2013.
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What Is ER+ Breast Cancer?
● Breast cancer tumors can be
characterized by the
presence or absence of
specific receptors, including:
– Estrogen receptor (ER)
– Progesterone receptor (PR)
– Human epidermal growth
factor receptor 2 (HER2)
● 2 out of 3 US women with
breast cancer are hormone
receptor-positive (HR+), with
cancerous cells that express
ER (ER+) and/or PR (PR+)
– Growth of ER+ breast cancer
is driven by estrogen
American Cancer Society. www.cancer.org/acs/groups/cid/documents/webcontent/003090-pdf.pdf. Accessed December 16, 2013.
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Treatment Options for ER+ Breast Cancer
● Treatment options for ER+ breast
cancer include local therapy
(eg, surgery, radiation therapy) and
systemic therapy (eg, chemotherapy,
endocrine/hormonal therapy)1,2
● Hormonal therapy can be used as
recommended for women with
ER+ breast cancer and is used as1,2:
– Adjuvant treatment
– Neoadjuvant treatment
– Treatment of metastatic
breast cancer
● When selecting a hormonal therapy,
a woman’s menopausal status is
taken into consideration1,2
Aromatase Inhibitors (AIs) decrease
the amount of available estrogen by
inhibiting the conversion of androgens
to estrogen, a primary source of
estrogen in post-menopausal women1,2
Antiestrogens prevent estrogen from
binding to the ER, regardless of
estrogen source, and may be
used to treat women prior to
or after menopause1,2
1. American Cancer Society. www.cancer.org/acs/groups/cid/documents/webcontent/003090-pdf.pdf. Accessed December 16, 2013; 2. National Cancer
Institute. www.cancer.gov/cancertopics/factsheet/Therapy/hormone-therapy-breast. Accessed December 19, 2013.
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Examples of Hormonal Therapies for ER+
Breast Cancer (and Year of FDA Approval)
Letrozole3
(1997)
Fulvestrant6
(2002)
Toremifene4
(1997)
Tamoxifen1
(1977)
1980
, antiestrogen;
Anastrozole2
(1995)
1990
1995
Exemestane5
(1999)
2000
2010
2014
, aromatase inhibitor.
1. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed January 27, 2014; 2. Arimidex [package insert].
Wilmington, DE: AstraZeneca Pharmaceuticals; 2013; 3. Femara [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2014; 4. Fareston [package insert].
Bridgewater, NJ: ProStraken Inc.; 2012; 5. Aromasin [package insert]. New York, NY: Pfizer Inc; 2013. 6. Faslodex [package insert]. Wilmington, DE: AstraZeneca
Pharmaceuticals; 2012.
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Role of CDK4/6 in Normal
and Tumor Cells
Cell Cycle Overview
●
●
●
Cellular proliferation is largely controlled by
extracellular factors that trigger progression
through the cell cycle1,2
The cell cycle consists of 4 highly regulated
phases1,2:
–
G1: cell growth and checkpoint for S phase
–
–
S: DNA synthesis
G2: cell growth and checkpoint for M phase
–
M: mitosis, cell division
In G1, CDK4/6 activation is required for
progression to and passage through the
critical Restriction point (R point), when cells
commit to pass through the remaining G1
phase and complete the cell cycle1,2
–
CDK4/6 are serine/threonine kinases that
function in the nucleus, and whose activity
depends on forming a complex with a
regulatory subunit, called cyclin D11,2
1. Sotillo E, Graña X. In: Cell Cycle Deregulation in Cancer 2010:3-22; 2. Weinberg RA. In: The Biology of Cancer; 2014:275-329.
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CDK4/6:
Downstream Cell Cycle Regulators
● The expression of cyclin D1—a protein
that preferentially binds to and activates
CDK4/6—is induced by mitogenic
growth factors, acting through various
upstream signaling pathways1
– Cyclin D1 is a direct transcriptional
target of ER2
● These multiple signaling pathways,
including mitogen-activated protein
kinase (MAPK), phosphatidylinositol
3-kinase (PI3K), and ER, converge
downstream at the cyclin D1-CDK4/6
complex, leading to its activation3
1. Weinberg RA. In: The Biology of Cancer; 2014:275-329; 2. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77;
3. Sotillo E, Graña X. In: Cell Cycle Deregulation in Cancer; 2010:3-22
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Role of CDK4/6 in Normal Cells
● Once activated, CDK4/6 lead to
phosphorylation (Figure A) and thus
inactivation of the retinoblastoma
protein (RB; Figure B), which is1,2:
A A
– A key tumor-suppressor protein
– A critical target of cyclin D1-CDK4/6
● Inactivated RB releases key
transcription factors (E2F; Figure B),
allowing expression of several genes
whose protein products are
necessary for S-phase entry and
DNA replication1,2
P
B
B
, phosphorylation.
1. Sotillo E, Graña X. In: Cell Cycle Deregulation in Cancer; 2010:3-22; 2. Fry DW, et
al. Mol Cancer Ther. 2004;3(11):1427-1438.
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Role of CDK4/6 in Tumor Cells
Dysregulation of the
cyclin D1-CDK4/6-RB
pathway occurs in many
human cancers
CDK4/6 activation leads to
increased RB phosphorylation
and cell cycle progression
This loss of proliferative
control is a hallmark of
tumor growth
Weinberg RA. In: The Biology of Cancer; 2014:275-328.
13
Role of CDK4/6 in
ER+ Breast Cancer
CDK4/6: Downstream Targets
of ER Signaling in ER+ Breast Cancer
● ER+ breast cancer exhibits a
high frequency of cell cycle
dysregulation due to aberrant
expression of key regulators1
– The increased expression of
cyclin D1 is frequently observed
in ER+ breast cancer,2,3 which
may lead to increased CDK4/6
activity
● CDK4/6 are downstream
targets of ER signaling in ER+
breast cancer1,4
– Estrogen induces cyclin D1CDK4/6 activation, which leads
to RB phosphorylation and cell
cycle progression4,5
1. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77; 2. Gillett C, et al.
Cancer Res. 1994;54(7):1812-1817; 3. Hui R, et al. Clin Cancer Res.
1996;2(6):923-928; 4. Weinberg RA. In: The Biology of Cancer; 2014:275329; 5. Kilker RL, et al. J Steroid Biochem Mol Biol. 2004;92(1-2):63-71.
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Synergistic Potential of Dual Inhibition
in ER+ Breast Cancer Cell Lines
Inhibition of
upstream ER
signaling arrests
ER+ breast cancer
tumor cells in the
G1 phase1
Potential synergistic
effect2
Inhibition of
downstream
CDK4/6 restores
cell cycle control,
restricting growth
of ER+ breast
cancer cell lines in
the G1 phase2
1. Sutherland RL, Musgrove EA. Breast Cancer Res. 2009;11(6):112; 2. Finn RS et al. Breast Cancer Res. 2009;11(5):R77.
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Summary
● Breast cancer is one of the most common cancers in US
women
– 250,000 women in the United States are living with advanced
breast cancer
● Approximately 2 out of 3 women with breast cancer in the
United States have hormone receptor-positive disease
● CDK4/6 inhibition, and the role it may play in restoring cell
cycle control in cancer, are critical areas of study
● Research is focusing on the dual inhibition of ER and
CDK4/6 in breast cancer
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