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Focus on HER2 as a therapeutic target

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Strategies for targeting HER2

Strategies for targeting HER2
HER2 is unique among the HER family receptors in that there are no known ligands that bind to it. Furthermore, HER2 is the preferred dimerization partner for all HER family receptors. Therefore, HER2 therapeutic targets include the extracellular portion of the receptor, HER2 dimerization, the intracellular tyrosine kinase domain of the receptor, and downstream signaling pathways.2,27

HER pathways have potential as therapeutic targets

HER2 has been successfully targeted in breast cancer. In ovarian cancer, HER2 is being investigated as a potential therapeutic target. There are several possible ways to target HER2. Note that targeting a ligand is inappropriate, since there are no known ligands that bind to HER2.2

Targeting the extracellular domain of HER2

The extracellular domain of HER2 is in a conformation that is open and ready for dimerization. However, it can be targeted in order to prevent receptor activation.2

  • Molecules such as monoclonal antibodies would bind to the extracellular domain of HER2 to suppress its activity28
    • This would prevent phosphorylation of the tyrosine kinase domain of HER2 and therefore preclude the initiation of downstream signaling pathways
    • Monoclonal antibodies may also trigger an immune response to cancer cells

Targeting HER2 dimerization

HER2 is the preferred dimerization partner for all HER family receptors. Therefore, preventing the dimerization of HER2 has the potential to affect multiple signaling pathways.2

  • Molecules such as monoclonal antibodies would bind to the extracellular domain of HER2, preventing it from dimerizing with other HER family receptors
    • This would prevent activation of HER2-containing dimers and their associated downstream signaling pathways28
    • By preventing HER2/HER3 dimers in particular, this strategy may address the potential for tumor cells to escape other HER2 inhibition strategies through HER2/HER3 dimerization4

Targeting the intracellular domain of the receptor

The tyrosine kinase domain of HER2 is located within the cell membrane and might also be a therapeutic target.

  • Small molecules can prevent transphosphorylation of the tyrosine kinase domain of HER24
    • Without transactivation of dimerized receptors, downstream signaling pathways are not initiated
    • These molecules could be specific to HER2, but might also act on the tyrosine kinase domain of other cellular receptors

Targeting downstream signaling pathways


  • Targeting molecules in the downstream signaling cascade that occurs after HER2-containing dimers have been activated is also a potential therapeutic strategy

 

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