Increased activation of ErbB and NF‐κB signalling pathways in Darier disease affected skin

Dear Editor,

Darier disease is a rare, autosomal dominant genetic skin disorder caused by mutations in the ATP2A2 gene, which encodes sarcoendoplasmic reticulum Ca²⁺‐ATPase isoform 2 (SERCA2). ¹ The condition is characterized by impaired keratinocyte adhesion, acantholysis and abnormal keratinization. ¹ Clinically, patients suffer from hyperkeratotic plaques, severe pruritus and secondary infections, all of which significantly impair quality of life. Despite various treatment options, efficacy remains limited, and no curative therapy is available. ²

We describe the case of a 43‐year‐old woman with a 28‐year history of Darier disease, who showed limited response to multiple therapies, including isotretinoin, acitretin, alitretinoin, naltrexone, topical corticosteroids and antiseptics. She presented with widespread hyperkeratotic plaques on the legs and disseminated papules affecting over 70% of her body surface. The patient reported persistent pruritus, reflected in a Dermatology Life Quality Index (DLQI) score of 23 (Figure 1a).

FIGURE 1.

Kinases in ErbB, NF‐kB and chemokine signalling pathways significantly affected in Darier disease lesions. (a) Clinical photograph of the patient of her lower legs with hyperkeratotic plaques. (b) Multiplex kinase activity profiling of Darier disease skin evaluated by using the PamGene technology, which is based on the measurement of peptide phosphorylation by tyrosine (Tyr) as well as serine/threonine (Ser/Thr) kinase activity (Image modified from Pamgene kinase brochure). (c,d) The proteomap shows the most altered kinases, represented as polygon‐shaped tiles, with their mean kinase statistics. Proteins within the same category are colour‐coded in a similar way and arranged next to each other to form larger regions. The size of each polygon is proportional to the extent of the change. The upper plot shows the activity of all kinases that are increased in lesional Darier's disease skin (c), while the lower plot shows kinases with decreased activity (d). (e) Kinome tree plot depicting distinct activation patterns of tyrosine and serine/threonine kinases, based on the mean kinase statistic (generated using CORAL).

Based on prior reports suggesting benefits of JAK inhibitors in Darier disease, treatment with upadacitinib (30 mg/day), a JAK1 inhibitor, was initiated. However, within 3 weeks, the patient developed eczema herpeticum, and no clinical improvement was observed. Due to the adverse event and lack of efficacy, the treatment was discontinued.

To identify novel therapeutic targets in this treatment‐refractory case, we performed multiplex functional kinase activity profiling (PamGene, Netherlands), assessing up to 150 kinases in lesional versus non‐lesional skin. The goal was to better understand the molecular mechanisms involved and uncover potentially targetable pathways. Two 5‐mm punch biopsies were taken from lesional and non‐lesional skin of the left thigh, and kinase activity was analysed using the PamChip^®4 platform (Figure 1b). ³

Kinome mapping via proteomap (Figure 1c,d) and kinome tree visualization (Figure 1e) ⁴ , ⁵ revealed increased activity of tyrosine kinases‐particularly ErbB3, Src and Syk‐linked to ErbB and NF‐κB signalling. Conversely, kinases in calcium signalling, MAPK and downstream ErbB pathways showed reduced activity. JAK kinases did not exhibit differential activation. Pathway enrichment analysis using the ClusterProfiler R package ⁶ highlighted the ErbB signalling pathway (Figure 2a) as the most significantly enriched.

FIGURE 2.

ErbB pathway is the most affected signalling pathway in Darier disease. (a) Top 10 pathways from gene enrichment analysis based on the KEGG database. (b) Top 10 pathways from gene enrichment analysis based on the Reactome database. (c) ErbB pathway diagram based on KEGG database. Kinases with increased activity in Darier disease were labelled red, while kinases with decreased activity were labelled blue (generated using paintomics).

ErbB receptors are membrane‐bound tyrosine kinases that, upon ligand binding, activate downstream pathways such as RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Src and STATs. ⁷ These regulate processes including proliferation, differentiation, apoptosis and senescence. ⁸ The ErbB family is well‐established in cancer biology and considered a key therapeutic target. ⁷ , ⁹ Our findings suggest that targeting ErbB signalling could be a viable therapeutic strategy for Darier disease. This aligns with transcriptomic data from SERCA2‐deficient keratinocytes, which showed elevated EGFR and MAPK pathway activity. Notably, MEK inhibitors improved keratinocyte cohesion and reduced tissue disruption in these models, though clinical data on MEK inhibitors in Darier disease is lacking.

Recent studies also implicate IL‐17 and IL‐12/IL‐23 pathways in Darier‐related inflammation. ¹⁰ These may intersect with SERCA2 and ErbB signalling via two mechanisms: (1) SERCA2's role in V(D)J recombination during B‐cell development, affecting immune regulation ¹⁰ ; and (2) disrupted epidermal integrity promoting dysbiosis and chronic Th17‐mediated inflammation. ¹⁰

However, our analysis has several limitations. It is based on a single patient, lacks comparison to healthy controls and uses a targeted kinase panel, which restricts analysis to well‐characterized kinases. These constraints may bias enrichment results and limit broader applicability.

Taken together, our data suggest that analysis of kinase activity could improve our understanding of the pathogenesis of different diseases and help identification of novel druggable targets and new treatment options, paving the way for personalized treatment approaches. Given the PamGene platform's reliance on predefined peptides, variability in signal quality and the single‐patient nature of this analysis, these findings should be interpreted with caution and validated in larger cohorts.

FUNDING INFORMATION

This work was supported by the Cluster of Excellence Precision Medicine in Chronic Inflammation (EXC 2167), the Collaborative Research Center ‘PANTAU’ (SFB 1526), funded by the Deutsche Forschungsgemeinschaft and the Schleswig–Holstein Excellence Chair Program from the State of Schleswig‐Holstein.

CONFLICT OF INTEREST STATEMENT

The authors declare no relevant conflict of interest.

ETHICAL APPROVAL

This study used the data generated during an individual treatment attempt and is thus exempt from institutional board review. Skin biopsies and photographs were taken after written informed consent from the patient.

ETHICS STATEMENT

The patients in this manuscript have given written informed consent to publication of their case details.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon request.