Epidermolysis bullosa simplex (EBS) is a severe and potentially life-threatening disorder for which no adequate
therapy exists. Most cases are caused by dominant sequence variations in
keratin genes K5 or K14, leading to the formation of cytoplasmic
keratin aggregates, profound keratinocyte fragility, and cytolysis. We hypothesized that pharmacological reduction of
keratin aggregates, which compromise keratinocyte integrity, represents a viable strategy for the treatment of EBS. In this study, we show that the multikinase inhibitor
PKC412, which is currently in clinical use for
acute myeloid leukemia and advanced
systemic mastocytosis, reduced
keratin aggregation by 40% in patient-derived K14.R125C EBS-associated keratinocytes. Using a combination of epithelial shear stress assay and real-time impedance spectroscopy, we show that
PKC412 restored intercellular adhesion. Molecularly, global phosphoproteomic analysis together with immunoblots using phosphoepitope-specific
antibodies revealed that
PKC412 treatment altered phosphorylated sites on
keratins and
desmoplakin. Thus, our data provide a proof of concept to repurpose existing drugs for the targeted treatment of EBS and showcase how one broad-range
kinase inhibitor reduced
keratin filament aggregation in patient-derived EBS keratinocytes and the fragility of EBS cell monolayers. Our study paves the way for a clinical trial using
PKC412 for systemic or local application in patients with EBS.