Cutaneous adverse drug reactions (CADR) associated with oncology treatments targeting proliferative cells impact healthy keratinocytes. Consequences include disturbance of epidermal structure and skin barrier dysfunction. CADR involve 45–100% of patients receiving kinase inhibitors and can significantly affect the patients’ quality of life. To prevent skin disorders as papulopustular rash at the face and upper trunk, xerosis, paronychia, loss of hair and more severe symptoms, a dose modification or drug discontinuation is required, disturbing the oncology treatment protocol.
We selected 6 drugs from first drug generation of Epidermal Growth Factor Receptor inhibitors (EGFRi) and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) and second or third generation drug treatment targeting main mutations leading to first generation treatment resistance. The effect of such inhibitors at physiological concentrations (3-10-30-100nM) corresponding to the unbound drug fraction in the plasma was studied using a reconstructed human micro-epidermis model. The drug impact was assessed by analysis of keratinocyte proliferation using Ki67 staining and keratinocyte differentiation using filaggrin, desmoglein and involucrin staining.
Results showed that all EGFRi have a dose dependent impact on keratinocyte differentiation by promoting filaggrin, desmoglein and involucrin expression in the different epidermis layers, moreover, the micro-epidermis size was mildly but significantly decreased and no staining of Ki-67 was observed. A higher drug concentration above 1µM was toxic leading to epidermal necrosis. VEGFRi contribute slightly to keratinocytes proliferation but there was no impact on keratinocyte differentiation markers, or the size of the micro-epidermis. 
To conclude, oncology treatment using EGFRi directly affects basal keratinocytes growth switching keratinocytes from a proliferative to a differentiative phenotype and tissue size reduction leading to barrier defect and skin impairment. VEGFRi barely affect keratinocyte differentiation and promote proliferation.

Cutaneous adverse drug reactions of oncology treatments