EGFR inhibitors in cancer treatment may be associated with adverse cutaneous events

A number of epidermal growth factor receptor inhibitors used in the oncology setting continue to demonstrate impacts on keratinocyte growth and cause adverse skin reactions, according to a study.

“Cutaneous adverse drug reactions associated with oncology therapy involve 45% to 100% of patients receiving kinase inhibitors,” Nicolas Joly-Tonetti, of Johnson & Johnson Santé Beauté France, and colleagues wrote.

Skin inflammation and infections are among the reactions that may occur, along with pruritis and dryness. These effects can have an impact on patient quality of life.

Clinicians frequently must adjust drug dosing or discontinue medications to prevent these events. However, this can affect oncology treatment protocols and possibly oncologic outcomes.

Epidermal growth factor receptor (EGFR) inhibitors targeting carcinomas have shown a particularly concerning trend toward adverse cutaneous effects, according to the researchers. They added that the EGFR pathway is integral to epidermal keratinocytes.

Due to this association, it may be a reasonable hypothesis that EGFR inhibitors interfere not only with the epidermal structure formation, but also with the skin barrier function.

In the study, the researchers used a novel 3D micro-epidermis tissue culture model to evaluate the impacts of EGFR inhibitors and VEGF receptor (VEGFR) inhibitors at the therapeutically relevant concentrations of 3 nM, 10 nM, 30 nM and 100 nM.

EGFR inhibitors that underwent analysis included gefitinib, erlotinib, afatinib, lapatinib, dacomitinib and osimertinib, while the VEGFR inhibitors were sunitinib and sorafenib.

Results for EGFR inhibitors showed decreased Ki67 staining, along with increases in filaggrin, desmoglein-1 and involucrin expression, compared with control. The cause for these effects may be that EGFR inhibitors “directly affect basal keratinocyte growth,” which can yield reduction in tissue size and the switching of keratinocytes from “a proliferative to a differentiative phenotype,” the researchers wrote.

Skin barrier impairment occurred. This finding was observed using a reconstructed model of the human epidermis that offered evidence of a decrease in transepidermal water loss rates.

Conversely, VEGFR inhibition had little impact on keratinocyte differentiation. In addition, these drugs promoted a proliferative phenotype.

“This study contributes to the mechanistic understanding of the clinically observed [cutaneous adverse drug reactions] during therapy with EGFR [inhibitors],” the researchers wrote. “These in vitro results suggest a specific mode of action of EGFR [inhibitors] by directly affecting keratinocyte growth and barrier function.”