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Focus on HER3 dysregulation
Slide Deck
View the HER3 slide deck
HER3 is an important partner in HER signaling pathways
HER3 plays a distinct role in the HER family signaling network. Although it is kinase inactive and therefore incapable of initiating downstream signaling pathways on its own, HER3 can dimerize with other receptors, particularly HER2, for potent cellular signaling. Evidence is growing to show that the transactivating nature of HER3 is an essential aspect of oncogenic function of the related receptors HER1/EGFR and HER2.1-3 Adapted by permission from Macmillan Publishers Ltd: BRITISH JOURNAL OF CANCER. Hsieh AC, Moasser MM. Br J Cancer. 2007;97:453-457, copyright 2007.
Biology of HER3
- HER3 can bind multiple ligands, such as heregulin and the neuregulins4,5
- HER3 lacks intrinsic tyrosine kinase activity6
- Because HER3 is kinase inactive, the receptor can only initiate signal transduction when dimerized with another HER family member
HER3 is necessary for HER2-mediated tumorigenesis
Although HER2-mediated tumorigenesis has been studied for over 20 years, the significance of HER3 as a necessary component of this process is only now beginning to be understood.
- HER2 requires HER3 in order to transform normal cells into cancer cells1
- Increased expression of HER3 increases the signaling potency of HER2, whereas decreased HER3 expression results in the loss of HER2 activity
- HER3 is involved in HER2-mediated tumorigenesis through dimerization with HER21
- HER3 enables HER2 to activate the PI3K signaling pathway1
- PI3K may lead to a more aggressive cellular phenotype7
- HER2 increases signaling potency, making the HER2/HER3 heterodimer a particularly effective initiator of PI3K7
HER3 may enable escape from inhibition of other HER receptors
Preclinical research has shown that upregulation of HER3 activity is a mechanism by which tumor cells can escape tyrosine kinase inhibition of HER family receptors.
- Tumor cells compensate for tyrosine kinase inhibition of other HER receptors by increasing expression of HER3, which is kinase inactive6
- In HER2/HER3 heterodimers, HER2 transphosphorylates HER36
- When HER2 is targeted using a tyrosine kinase inhibitor, tumor cells can compensate by upregulating HER3 activation
- When HER3 activation is upregulated, it becomes more difficult to reverse the process of HER2/HER3 phosphorylation
- HER2/HER3 heterodimers thus remain active, preserving downstream signaling pathways even in the presence of tyrosine kinase inhibition6
