Unlocking the mechanisms of Cutaneous Adverse Drug Reactions: Activation of the PI3K/AKT pathway by EGFR inhibitors triggers keratinocyte differentiation and polarization of epidermal immune responses


Epidermal Growth Factor inhibitors (EGFRi) used in oncology therapy modify the keratinocyte differentiation processes, impairing proper skin barrier formation and leading to Cutaneous Adverse Drug Reactions (CADR). To uncover the molecular signatures associated with CADRs, we applied phospho-proteomic and transcriptomic assays on Reconstructed Human Epidermis (RHE) tissues exposed to a therapeutically relevant concentration of afatinib, a second EGFRi generation. Following drug exposure, we observed activation of the PI3K/AKT pathway associated with an increased expression of gene families involved in keratinocyte differentiation, senescence, oxidative stress and alterations in the epidermal immune-related markers. Furthermore, our results show that afatinib may interfere with Vitamin D3 (VD3) metabolism, acting via CYP27A1 and CYP24A1 to regulate calcium concentration through the PI3K/AKT pathway. Consequently, basal layer keratinocytes switch from a pro-proliferating to a pro-differentiative program, characterized by upregulation of biomarkers associated with increased keratinization, cornification, Th2 response and decreased innate immunity. Such effects may increase the skin susceptibility to cutaneous penetration of irritants and pathogens. Taken together these findings demonstrate a molecular mechanism of EGFRi-induced CADRs.

In JID Innovations