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Focus on the therapeutic potential of HER pathways

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There are multiple ways to target HER pathways

There are multiple ways to target HER pathways
Because HER signaling pathways are extremely complex, they can be targeted using several different strategies.

Ligands that bind to HER receptors, the extracellular ligand-binding domain of a HER family receptor, the intracellular tyrosine kinase domain of the receptor, and downstream molecular signals can all be targeted.1,5

HER pathways have potential as therapeutic targets in many tumor types

Because of their involvement in tumor biology, HER family receptors and their associated signaling pathways represent potential therapeutic targets. A number of strategies could be utilized to target HER pathways.

Targeting the ligand

One possible strategy involves molecules that would target ligands specific to HER family receptors.

  • This strategy would prevent ligands from binding to their associated receptors, thus preventing the activation of signaling pathways1
  • Note that HER2, the preferred dimerization partner for HER family receptors, does not bind ligands1
    • Therefore, the strategy of targeting ligands may not be ideal

Targeting the extracellular domain of the receptor

The extracellular domain of a HER family receptor, which binds ligands (with the exception of HER2), represents another possible therapeutic target.

  • Molecules such as monoclonal antibodies would bind to the extracellular domain of a HER family receptor, either suppressing receptor activity or preventing receptor dimerization12
    • This would prevent phosphorylation of the tyrosine kinase domain of the receptor and therefore preclude the initiation of downstream signaling pathways
    • These molecules are specific to a single type of HER family receptor
    • Monoclonal antibodies may also trigger an immune response to cancer cells

Targeting the intracellular domain of the receptor

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

  • Small molecules can prevent transphosphorylation of the tyrosine kinase domain of dimerized HER family receptors13
    • Without transactivation of dimerized receptors, downstream signaling pathways are not initiated
    • These molecules could be specific to a single type of HER family receptor or have broader activity

Targeting downstream signaling pathways

Targeting molecules in the downstream signaling cascade that occurs after HER family receptors have been activated is also a potential therapeutic strategy.

  • HER family receptor dimers often initiate multiple downstream signaling pathways1
    • Each of these pathways might require a different molecule for therapeutic inhibition

 

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