EGFR inhibitors switch keratinocytes from a proliferative to a differentiative phenotype affecting epidermal...

Area of Science:

• Oncology
• Dermatology
• Pharmacology

Background:

• Cutaneous adverse drug reactions (CADR) affect 45-100% of patients on kinase inhibitors, impacting quality of life and treatment adherence.
• Epidermal Growth Factor Receptor inhibitors (EGFRi) are frequently associated with CADR, particularly in carcinoma treatment.
• The EGFR pathway's role in epidermal keratinocytes suggests EGFRi may disrupt skin structure and barrier function.

Purpose of the Study:

• To investigate the direct effects of EGFR inhibitors on human keratinocytes.
• To elucidate the mechanistic basis of CADR associated with EGFR inhibitors.
• To compare the effects of EGFR inhibitors and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) on keratinocyte behavior.

Main Methods:

• Utilized a novel 3D micro-epidermis tissue culture model.
• Assessed proliferation and differentiation markers of human keratinocytes.
• Tested therapeutically relevant concentrations (3-100 nM) of EGFRi and VEGFRi.

Main Results:

• EGFRi reduced tissue size and shifted keratinocytes from proliferation to differentiation (decreased Ki67, increased filaggrin, desmoglein-1, involucrin).
• EGFRi treatment led to skin barrier impairment, evidenced by decreased transepidermal water loss.
• VEGFR inhibitors showed minimal impact on keratinocyte differentiation and promoted proliferation.

Conclusions:

• EGFRi directly impact keratinocyte growth and skin barrier function.
• This study provides mechanistic insights into CADR observed during EGFRi cancer therapy.
• In vitro findings highlight a specific mode of action for EGFRi on epidermal integrity.