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.

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.

HER2 is always in an open conformation making it an ideal dimerization partner

HER2

HER2 does not require a ligand to be primed

Garrett et al. Mol Cell. 2003;11:495-505. Graus-Porta et al. EMBO J. 1997;16:1647-1655.

Among all possible dimers, the HER2:HER3 pair has the strongest mitogenic signaling

Homodimers
HER3:HER3 HER2:HER2 HER1:HER1 HER4:HER4 HER1:HER2

Heterodimers
HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4

+ +

+ + + + + + + + +
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Signaling activity
Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397.

Phosphorylation of the tyrosine kinase domains of HER dimer pairs is regulated via allosteric interactions

Zhang et al. Cell. 2006;125:1137-1149.

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

Unmet need in the HER2(+) metastatic breast cancer (MBC) population
*Combined metastatic and adjuvant patients.
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HER2(+) protein overexpression by IHC

Slamon et al. Science. 1987;235:177-182. Pauletti et al. J Clin Oncol. 2000;18:3651-3664.

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.

HER3, but not HER1, plays a critical role in proliferation of HER2-overexpressing breast cancer cells in vitro
180 Cell proliferation relative [3H]thymldine uptake (% of control) 160 140 120 100 80 60 40 20 0 BT474 HCC1419 SKBR3 ZR-75-30 EFM192A HCC1954

HER2(+) cell lines

Genes silenced Control HER1 HER2 HER3

Lee-Hoefflich et al. Cancer Res. 2008;68:5878-5887.

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

P P P

PI3K
P

P P

AKT

PDK1

Raf

GSK3
mTOR MEK Cyclin D1 p27 BAD

NFB

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 mAbs 9
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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