HER2 HER3 Dimerazation

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 angiogenesis^1,2
  • 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

    
• HER3 can dimerize with other receptors, particularly ligand-inactive HER2, to mediate downstream signaling pathways^5,6
• 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

  

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 cancer^8-10
  • 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–amplified breast cancer

      
  • 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