Abstract
BackgroundCutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45–100% of patients receiving kinase inhibitors. Such adverse reactions may include skin inflammation, infection, pruritus and dryness, symptoms that can significantly affect the patient’s quality of life. To prevent severe skin damages dose adjustment or drug discontinuation is often required, interfering with the prescribed oncology treatment protocol. This is particularly the case of Epidermal Growth Factor Receptor inhibitors (EGFRi) targeting carcinomas. Since the EGFR pathway is pivotal for epidermal keratinocytes, it is reasonable to hypothesize that EGFRi also affect these cells and therefore interfere with the epidermal structure formation and skin barrier function.MethodsTo test this hypothesis, the effects of EGFRi and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) at therapeutically relevant concentrations (3, 10, 30, 100 nM) were assessed on proliferation and differentiation markers of human keratinocytes in a novel 3D micro-epidermis tissue culture model.ResultsEGFRi directly affect basal keratinocyte growth, leading to tissue size reduction and switching keratinocytes from a proliferative to a differentiative phenotype, as evidenced by decreased Ki67 staining and increased filaggrin, desmoglein-1 and involucrin expression compared to control. These effects lead to skin barrier impairment, which can be observed in a reconstructed human epidermis model showing a decrease in trans-epidermal water loss rates. On the other hand, pan-kinase inhibitors mainly targeting VEGFR barely affect keratinocyte differentiation and rather promote a proliferative phenotype.ConclusionsThis study contributes to the mechanistic understanding of the clinically observed CADR during therapy with EGFRi. These in vitro results suggest a specific mode of action of EGFRi by directly affecting keratinocyte growth and barrier function.
Highlights
Cutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45–100% of patients receiving kinase inhibitors
Patients who initially respond to the Tyrosine kinase inhibitors (TKi) will generate resistance due to mutations within the 9 to 13 months following the initiation of their therapy, requiring a switch of the therapeutic regiment to address the appearance of such mutations [5, 6]
In order to better understand the emergence of CADRs, we examined in this work the effects of TKi on the epidermal physiology and the eventual consequences on the quality of the skin barrier against external irritant and pathogen penetration and water loss
Summary
Cutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45–100% of patients receiving kinase inhibitors. To prevent severe skin damages dose adjustment or drug discontinuation is often required, interfering with the prescribed oncology treatment protocol This is the case of Epidermal Growth Factor Receptor inhibitors (EGFRi) targeting carcinomas. The epidermis consists of a stratified epithelium, mainly composed of keratinocytes It provides the first defense of the host against external aggressors including pathogens and prevents dehydration by controlling the rate of transcutaneous water loss. Since the epidermal epithelium normally includes proliferative cells, it is reasonable to hypothesize that it becomes a target of such therapies [1], a process that can lead to Cutaneous Adverse Drug Reactions (CADR) as consequence of defective epidermal differentiation, alteration of skin equilibrium and barrier dysfunction [2]. The third generation of EGFRi irreversibly inhibits EGFR despite the appearance of T790M mutation improving progression-free survival and reduction of CADR compared to standard chemotherapies [7, 8]
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