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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.

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There are four receptors in the Human Epidermal Receptor network

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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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