263 EGFR signalling is overactive in Pachyonychia congenita: effective treatment with oral erlotinib

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma (PPK), thickened nails and blistering for which there are no standard current treatment. PC caused dominant mutations in keratin 6A, 6B, 6C, 16 17 genes involved stress, wound healing epidermal barrier formation. Mechanisms leading to pain PPK remain elusive. To gain further insight into pathogenesis, we studied the human growth factor receptor (HER) pathway transient potential vanilloid-3 (TRPV3) expression calluses 3 patients. We report overexpression of EGFR ligands epiregulin TGFa as well HER1-EGFR HER2 upper spinous layers lesions. activation was confirmed upregulated mTOR signalling assessed increased p-RPS6. Abnormal late terminal keratinization associated with elevated transglutaminase-1 (TG1) activity. Additionally, Ca2+ permeable channel TRPV3 significantly PC-lesioned skin suggesting predominant role TRPV3/EGFR complex PC. hypothesized that this increases TG1 activity induces shedding ligands. counteract biological cascade, treated adult patients oral erlotinib 5-6 months. The treatment tolerated led an early, drastic sustained reduction neuropathic major improvement quality-of-life. Our study provides evidence EGFR/TRPV3 contributes pathogenesis pharmacological inhibition effective strategy treat plantar