There are four receptors in the human epidermal receptor network
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There are four receptors in the Human Epidermal Receptor network. HER1/EGFR. HER2. HER3. HER4. HER2 and HER3 are not fully competent but their functions are highly complementary to each other. EGFR = epidermal growth factor receptor. Yarden, Sliwkowsky. Nat Rev Mol Cell Biol 2001;2:127–137.

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There are four receptors in the Human Epidermal Receptor network

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There are four receptors in the human epidermal receptor network

There are four receptors in the Human Epidermal Receptor network

HER1/EGFR

HER2

HER3

HER4

HER2 and HER3 are not fully competent but their functions

are highly complementary to each other

EGFR = epidermal growth factor receptor

Yarden, Sliwkowsky. Nat Rev Mol Cell Biol 2001;2:127–137


Her2 her3 dimers have the strongest mitogenic signaling

HER2:HER3 dimers have the strongest mitogenic signaling

Homodimers

Heterodimers

HER1:HER2

HER1:HER3

HER4:HER4

HER1:HER4

HER3:HER3

HER2:HER3

HER2:HER2

HER2:HER4

HER1:HER1

HER3:HER4

Signaling activity

Tzahar et al. Mol Cell Biol 1996;16:5276–5287


Her2 dimerization is key to signaling activity

P

P

P

P

HER2 dimerization is key to signaling activity

Ligand-activatedHER2:HER3 dimer

HER2

HER3

Phosphorylation of the tyrosine kinase domain by HER2 initiates intracellular signaling

Ferguson et al. Mol Cell 2003;11:507–517. Olayioye et al. EMBO J 2000;19:3159–3167. Hynes et al. Nat Rev Cancer2005;5:341–354. Rowinsky. Annu Rev Med 2004;55:433–457


There are four receptors in the human epidermal receptor network

AKT

P

P

P

P

P

P

P

RAS

Sos

Grb2

Shc

PI3K

PDK1

Raf

GSK3ß

NFκB

mTOR

MEK

BAD

Cyclin D1

MAPK

p27

HER2 signaling results in a multitude of cellular effects, including increased cellular proliferation

HER2

HER3

Apoptosis

Survival

Cell cyclecontrol

Angiogenesis

Proliferation

Olayioye et al. EMBO J 2000;19:3159–3167. Rowinsky. Annu Rev Med 2004;55:433–457


Her2 targeted agents crossing the plasma membrane

AKT

AKT

Large molecules

Generally, large proteins (~150 000 Da)

Highly specific

Cannot penetrate through the plasma membrane

Flag cells for destruction by the immune system, eg, monoclonal antibodies (mAbs)

HER2-targeted agents:Crossing the plasma membrane

Small molecules

Generally, chemical agents (~400 Da)

Varying degrees of specificity

Penetrate through the plasma membrane

Cannot flag cells for destruction by the immune system, eg, lapatinib and other tyrosine kinases (TKIs)

P

P

P

P

P

P

RAS

RAS

Sos

Sos

Grb2

Grb2

Shc

Shc

PI3K

PI3K

PDK1

PDK1

Raf

Raf

Cell surface

receptors

Cell surface

receptors

Adjei et al. J Clin Oncol 2005;23:5386–5403

5


Binding to different regions on her2 and may have synergistic activity

Binding to different regions on HER2 and may have synergistic activity

HER2

HER3

Subdomain IV of HER2

Dimerization domain of HER2

  • Does not inhibit HER2 dimerization, thus blocking HER2:HER3

  • Prevents HER2 receptor shedding

  • Blocks HER2 signaling and flags cells for destruction by the immune system

  • Inhibits HER2 from forming dimer pairs

  • Flags cells for destruction by the immune system

  • Does not prevent HER2 receptor shedding


A broad blockade of the her2 pathway may be needed to prevent cancer cell progression

A broad blockade of the HER2 pathway may be needed to prevent cancer cell progression

HER2

HER3

Sergina et al, showed that blocking HER1 and HER2 with TKIs upregulates HER3 and HER2+ breast cancer cells progress

TKI

Sergina et al. Nature 2007;445:437–441


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