Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Skin toxicity is a frequent adverse event in cancer patients receiving epidermal growth factor receptor (EGFR)-targeted therapies.
• In contrast, HER2-targeted therapies rarely cause significant dermatologic side effects.

Purpose of the Study:

• To investigate the role of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) dimerization in skin toxicity.
• To elucidate the differential effects of HER-directed therapies on EGFR, HER2, and MAPK signaling in human keratinocytes.

Main Methods:

• Utilized normal human epidermal keratinocytes and skin tissue from cancer patients.
• Administered EGFR-directed (gefitinib, cetuximab) and HER2-directed (pertuzumab) therapies.
• Employed a novel proximity-based dimerization assay (eTag™) to assess HER dimer status.
• Analyzed ligand-induced activation of EGFR, HER2, and MAPK signaling pathways.

Main Results:

• EGFR-directed therapies inhibited ligand-induced activation of EGFR and MAPK.
• Pertuzumab did not block ligand-induced HER signaling in primary keratinocytes.
• EGFR homodimers were identified as the predominant HER dimer pair in normal keratinocytes and skin.
• Signaling via EGFR (indicated by [p]EGFR and [p]MAPK) was productive in human skin, while HER2 signaling was not ([p]HER2 absent).

Conclusions:

• EGFR homodimer signaling, rather than EGFR/HER2 heterodimer signaling, is crucial for dermatologic toxicity in human skin.
• The specific dimerization partner of EGFR significantly influences the development of skin side effects.
• These findings may guide the development of targeted cancer therapies with reduced dermatologic toxicity.