O16 Erlotinib in pachyonychia congenita

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ID: 318416
2026
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Abstract
Abstract Introduction and aims Pachyonychia congenita (PC) is a rare inherited skin disorder within the palmoplantar epidermal differentiation disorders (pEDDs), recently reclassified by genotype as KRT6A/KRT6B/KRT6C/KRT16/KRT17-pEDD. Patients experience painful plantar calluses and severe, disabling foot pain. PC keratinocytes exhibit increased epidermal growth factor receptor (EGFR) expression. Erlotinib, an EGFR inhibitor approved for metastatic cancer in the UK, has shown anecdotal benefit in reducing pain and improving function in patients with PC (n = 6). This study aimed to assess the effect of erlotinib effects on PC-derived keratinocyte cell lines in two-dimensional and three-dimensional (3D) culture. Methods Western blot analysis was used to evaluate EGFR and its phosphorylation in wildtype (WT) and PC keratinocytes with and without EGF or erlotinib. 3D skin equivalents were generated for immunostaining of differentiation markers. Callus samples from a patient with KRT16-pEDD, pre- and post-erlotinib treatment (4 months), underwent phosphoproteomic analysis and pathway analysis. Results The KRT16-pEDD cell line demonstrated heightened EGF responsiveness and elevated baseline phospho-ERK. Erlotinib reduced p-ERK by 36% at 1–10 nmol L–1 and by 87% at 1 μmol L–1. In 3D models, KRT6A(N171K) epidermis showed acanthosis and disordered differentiation, which normalized at 100 nmol L–1 erlotinib, restoring involucrin to the upper epidermis. Phosphoproteomics revealed post-treatment changes in differentiation/cornification and BRAF pathway enrichment, indicating compensatory signalling following EGFR inhibition. Conclusions Erlotinib effectively attenuates EGFR signalling in PC keratinocytes, normalizing epidermal architecture and differentiation in 3D models. Phosphoproteomic changes suggest compensatory BRAF pathway activation, which may cause therapeutic resistance. These findings support EGFR inhibition as a potential therapeutic approach for PC and warrant placebo-controlled trials.
Reference Key
openalex_W7165621890 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Elena Giusto, Marianne de Brito, Edel O’Toole
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.016
URL
https://doi.org/10.1093/bjd/ljag151.016
Keywords Keywords not found

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