841 EGFR signalling contributes to pachyonychia congenita pathogenesis and its inhibition improves patients’ quality of life

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by thickened nails, painful and inflammatory palmoplantar keratoderma (PPK) blistering for which no standard treatment currently available. PC caused dominant mutations in keratin (KRT) 6A, 6B, 6C, 16 17 genes are involved wound healing epidermal barrier formation. Previous reports pointed to mTOR activation oxidative stress with dysfunctional NRF2 as contributors PPK. However, the relationship between KRT pathogenesis of pain PPK PC, remains elusive. Recent studies have shown that growth factor receptor (EGFR) regulation (OS) its inhibition prevents reactive oxygen species generation. We confirm NRF2, key regulator OS, hypophosphorylated lesional skin from 3 patients KRT6 or KRT16 mutations, indicating defective OS regulation. describe strong increase transglutamisase-1 activity expression directly induced EGFR signaling differentiating keratinocytes. Additionally, pathway was upregulated all patients, consistent activation. forms complex transient potential vanilloid-3 (TRPV3) modulation sensitivity pain. TRPV3 transcript levels were significantly increased hyperkeratotic lesions suggesting channels might connect nociception PC. inferred pharmacological be an effective approach treating Our preliminary results showed oral Erlotinib well tolerated led early, drastic sustained reduction major improvement quality life after few weeks treatment. Together, our suggest contributes provide evidence powerful strategy