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HER3 as a therapeutic target

Strategies for targeting HER3

Unlike other HER family receptors, HER3 is kinase inactive, so that directly targeting the tyrosine kinase domain of the receptor may not be useful. Targeting HER3 in other ways may be a potential therapeutic strategy.^2,6,19,20

HER3 is a potential therapeutic target

The association of HER3 with breast and ovarian cancer makes it a potential therapeutic target in those tumor types. There are several possible ways to target HER3. Note that the tyrosine kinase domain of HER3 has not been targeted in clinical development, since HER3 is kinase inactive.²

Targeting HER3 ligands

Several ligands, such as the neuregulins and heregulin, bind HER3.^4,5 Blocking heregulin expression inhibits tumorigenicity and metastasis of breast cancer cells.²¹ HER3 ligands could be potential therapeutic targets.

• Molecules such as monoclonal antibodies would bind to HER3 ligands, preventing them from binding to HER3
  • Note that HER3, in isolation, cannot be activated by a ligand because it is kinase inactive⁶

Targeting HER2:HER3 dimers

HER2:HER3 dimers have been shown to be a method by which tumor cells escape HER family kinase inhibition. Therefore, targeting the formation of these dimers is an additional therapeutic strategy.⁶

• Molecules such as monoclonal antibodies would bind to the extracellular domain of HER2, preventing it from dimerizing with HER3 and other HER family receptors²²
  • Prevention of HER2:HER3 dimers may address the potential for tumor cells to escape other HER2 inhibition strategies through HER2:HER3 dimerization⁶

Targeting downstream signaling pathways

• Molecules in the downstream signaling cascade that occurs after HER3-containing dimers have been activated are also potential therapeutic targets²