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Focus on HER1 dysregulation

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HER1/EGFR dysregulation has multiple effects on cancer cells

HER1/EGFR dysregulation has multiple effects on cancer cells
Binding of HER1/EGFR-specific ligands, such as epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) leads to receptor dimerization and transphosphorylation. Phosphorylated HER1/EGFR-containing dimers stimulate multiple downstream signaling pathways, leading to cellular effects such as increased proliferation and invasive ability, tumor angiogenesis, metastasis, and the ability to evade apoptosis.1 Adapted from Herbst et al, Clinical Cancer Research, 2003. Reprinted with permission from the American Association for Cancer Research.

Biology of HER1/EGFR


  • HER1/EGFR has an extracellular ligand-binding domain that can bind multiple ligands, such as EGF and TGF-α1
  • HER1/EGFR has an intracellular tyrosine kinase domain2
    • The tyrosine kinase domain is activated upon ligand binding and subsequent receptor dimerization
  • HER1/EGFR dimers are capable of activating multiple downstream signaling pathways1

How does HER1/EGFR signaling become dysregulated?

HER1/EGFR signaling may be inappropriately activated in cancer cells. This may occur in one of several ways.

  • Gene amplification means there are too many copies of the HER1/EGFR gene in the cell3
  • Receptor overexpression means an excess of receptors on the cell membrane3,4
    • An excess of receptors leads to increased HER1/EGFR pathway signaling1
  • Overexpression of ligands that bind to HER1/EGFR can also lead to an increase in signaling because more ligands are available to bind to receptors3,5
    • Tumor cells can overexpress both HER1/EGFR and its ligands, resulting in an autocrine signaling loop in which tumor cells stimulate their own growth and spread
  • A genetic mutation can lead to dysfunctional HER1/EGFR receptors3
    • These dysfunctional receptors may be able to initiate downstream signaling pathways even in the absence of ligand binding
    • Mutations that can lead to tumorigenesis include point mutations in exon 19 of the EGFR gene and changes in the related KRAS gene6,7

The effects of dysregulated HER1/EGFR signaling

The downstream signaling pathways initiated by activation of HER1/EGFR dimers have numerous effects on cancer cells, enabling them to grow and spread.

  • The PI3K signaling pathway promotes cell cycle progression and cellular survival3
  • The Ras/Raf/MEK/MAPK kinase pathway leads to increased tumor cell proliferation1,3
  • The STAT3 pathway induces gene transcription3
  • The FAK signaling pathway stimulates tumor cell migration3
  • Additional effects of dysregulated HER1/EGFR signaling include tumor angiogenesis, cellular invasion, and metastasis1

 

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