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HER2:HER3 dimer

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HER2:HER3 is a particularly potent signaling pair in preclinical models of HER2-positive breast cancer

  • Signals from dimerized, activated HER family receptors can impact different downstream signaling cascades, including the MAPK proliferation pathway and/or the PI3K/Akt survival pathway, leading to multiple effects, including growth, proliferation, decreased apoptosis, cellular migration, and angiogenesis1,2

    • HER2 overexpression occurs in about 25% of breast cancers3; these tumors frequently display activated HER34
    • HER3 is kinase inactive and therefore incapable of initiating downstream pathways on its own5

Differences between HER family receptors Differences between HER family receptors

  • HER3 can dimerize with other receptors, particularly ligand-inactive HER2, to mediate downstream signaling pathways5,6
  • Together, HER2 and HER3 form a potent transforming complex7
  • Increasing evidence demonstrates that the ability of HER3 to activate signaling pathways plays a key role in HER1/EGFR- and HER2-mediated tumorigenesis

The HER2:HER3 dimer pair is a potent transforming complex The HER2:HER3 dimer pair is a potent transforming complex

HER3 expression and HER2-amplified breast cancer

  • Emerging preclinical data suggest that a broader blockade of multiple HER family receptors may be therapeutically important in HER2-amplified breast cancer8-10
    • HER family tyrosine kinase inhibitors directed at HER1/EGFR and HER2 have shown limited antitumor activity in HER2-driven breast cancer cells9
    • Preclinical studies suggest that this may be due to HER3’s ability to escape HER1/EGFR and HER2 inhibition and thus propagate downstream prosurvival signaling9
    • When HER2 is targeted using a tyrosine kinase inhibitor, tumor cells can compensate by upregulating HER3 activation, making it more difficult to reverse the process of HER2:HER3 phosphorylation9
      • Thus, HER3 does not remain “turned off” after tyrosine kinase inhibitor treatment and is able to be phosphorylated, which allows for activation of the PI3K/Akt pathway9

HER3 may escape inhibition and mediate prosurvival pathways in HER2-amplifired breast cancer The HER2:HER3 dimer pair is a potent transforming complex

    • PI3K/Akt is a critically important tumorigenic signaling pathway5
      • Inhibition of Akt and MAPK phosphorylation may correlate with decreased tumor cell proliferation and increased apoptosis5
      • While HER2 cannot directly bind or activate PI3K/Akt, HER2-positive cancers exhibit increased Akt expression and phosphorylation5
      • HER3 is the principal HER family member that can activate the PI3K/Akt pathway directly9
  • These data emphasize the crucial role HER3 may play in HER2-driven cancers
  • In order to shut down multiple pathways in HER2-amplified breast cancer, a broad blockade that overcomes the complexities and resilience of the HER family may be necessary9

A broader inhibition of HER family receptors may be necessary to inhibit multiple pathways in HER2-driven breast cancer
A broader inhibition of HER family receptors may be necessary to inhibit multiple pathways in HER2-driven breast cancer

Next Section: HER2:HER3 dimer: ReferencesArrow

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