Download HER2(+)

The
HER2:HER3
dimer
A potent pair in HER2(+)
breast cancer
The human epidermal growth factor receptors (HER) are a
family of structurally-related cell surface proteins
Extracellular ligand-binding domain
HER1/EGFR
HER2
HER3
HER4
Transmembrane
domain
Intracellular tyrosine kinase domain
Rowinsky. Oncologist. 2003;8(suppl 3):5-17. Yarden et al. Nature Rev Mol Cell Biol. 2001;2:127-137.
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With the exception of HER2, HER proteins undergo a conformational
change upon ligand binding that is essential for dimerization and signaling
Ligand primes receptor
for activity
Closed conformation
Open conformation
Cho et al. Science. 2002;297:1330-1333. Ferguson et al. Mol Cell. 2003;11:507-517. Ogiso et al. Cell. 2002;110:775-787.
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HER2 is always in an open conformation making it an ideal
dimerization partner
HER2
Garrett et al. Mol Cell. 2003;11:495-505. Graus-Porta et al. EMBO J. 1997;16:1647-1655.
HER2 does not require a
ligand to be primed
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Among all possible dimers, the HER2:HER3 pair has the
strongest mitogenic signaling
Homodimers
HER3:HER3
Heterodimers
HER4:HER4
HER1:HER2
HER1:HER3
HER1:HER4
HER2:HER3
HER2:HER2
HER2:HER4
HER1:HER1
HER3:HER4
+
+
+
+
+
+
+ + +
+ + +
+ +
+
Signaling activity
Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397.
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Phosphorylation of the tyrosine kinase domains of HER
dimer pairs is regulated via allosteric interactions
Zhang et al. Cell. 2006;125:1137-1149.
6
In the absence of treatment, patients with HER2+ breast
cancer have shortened median survival
HER2 gene
amplification by FISH
Shortened median survival*
HER2(+)
3 years
HER2 normal
6 –7 years
HER2(+) protein overexpression
by IHC
Slamon et al. Science. 1987;235:177-182. Pauletti et al. J Clin Oncol. 2000;18:3651-3664.
Unmet need in the HER2(+)
metastatic breast cancer
(MBC) population
*Combined metastatic and adjuvant patients.
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Beyond HER2 overexpression: What is the role of other HER
proteins as dimerization partners in HER2(+) breast cancer?
Tsai et al. Oncogene. 2003;22:761-768. Sergina et al. Nature. 2007;445:437-441. Holbro et al. Proc Natl Acad Sci USA. 2003;100:8933-8938.
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HER3, but not HER1, plays a critical role in proliferation of
HER2-overexpressing breast cancer cells in vitro
HER2(+) cell lines
Cell proliferation
relative [3H]thymldine uptake
(% of control)
180
Genes silenced
Control
160
HER1
140
HER2
120
HER3
100
80
60
40
20
0
BT474
Lee-Hoefflich et al. Cancer Res. 2008;68:5878-5887.
HCC1419
SKBR3
ZR-75-30 EFM192A HCC1954
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HER2:HER3 trigger complementary oncogenic signals
Ligand-activated HER2:HER3 dimer
HER2
HER3
Phosphorylation of the tyrosine kinase
domain initiates intracellular signaling
Yarden et al. Nature Rev Mol Cell Biol. 2001;2:127-137. Holbro et al. Proc Natl Acad Sci USA. 2003;100:8933-8938. Tzahar et al. Mol Cell Biol. 1996;16:5276-5287.
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HER2 signaling results in a multitude of cellular effects, including
not only increased cellular proliferation, but also cell survival
HER2
HER3
RAS Sos Grb2 Shc
PI3K
P P
PDK1
P
P
AKT
P P
P
Raf
GSK3ß
NFκB
mTOR
MEK
BAD
Cyclin D1
p27
Apoptosis
MAPK
Cell cycle
control
Angiogenesis
Olayioye et al. EMBO J. 2000;19:3159-3167. Rowinsky. Oncologist. 2003;8(suppl 3):5-17.
Survival
Proliferation
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In preclinical models, a broad blockade of HER pathways
may be needed to prevent breast cancer cell progression
HER2
HER3
Blocking HER1 and HER2
with TKIs upregulates HER3
and HER2(+) tumor
cells progress
TKI
Control
HER1-directed TKI
Sergina et al. Nature. 2007;445:437-441.
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Summary

The complex network of ligands, receptor combinations, and effector molecules
ensures HER signal diversity and is essential for multiple cellular processes1

HER signaling deregulation has been associated with the development of numerous
malignancies. The overexpression of HER2 is strongly implicated in breast
cancer2,3,4

HER2 is the only HER protein that exists in a permanent open, ready-to-dimerize
conformation, a configuration essential for receptor signal transduction5

Emerging evidence suggests that HER3 is the primary signaling partner of HER2 in
breast cancer. This heterodimer triggers the strongest mitogenic signal of all
receptor dimer pairs and provides unique signaling via the PI3K/Akt survival
pathway6,7,8

HER2-mediated HER3 signaling may be responsible for the evasion of HER
signaling inhibition upon treatment of breast cancer cell lines with TKIs and mAbs9

This emerging data may have implications in the selection of adequate biomarkers
of HER oncogenic signaling activity, such as HER3 transactivation, and in the
development of more comprehensive targeted approaches capable of fully
abrogating HER oncogenic signaling via the HER2:HER3 dimer in preclinical
models10,11,12
TKI=tyrosine kinase inhibitor; mAb=monoclonal antibody.
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