title: EGFR inhibitors erlotinib and lapatinib ameliorate epidermal blistering in pemphigus vulgaris in a non-linear, V-shaped relationship.
abstract: Novel insights into intra-cellular signalling involved in pemphigus vulgaris (PV), an autoimmune blistering disease of skin and mucous membranes, are now revealing new therapeutic approaches such as the chemical inhibition of PV-associated signals in conjunction with standard immunosuppressive therapy. However, extensive inhibition of signalling molecules that are required for normal tissue function and integrity may hamper this approach. Using a neonatal PV mouse model, we demonstrate that epidermal blistering can be prevented in a dose-dependent manner by clinically approved EGFR inhibitors erlotinib and lapatinib, but only up to approximately 50% of normal EGFR activity. At lower EGFR activity, blisters again aggravated and were highly exacerbated in mice with a conditional deletion of EGFR. Statistical analysis of the relation between EGFR activity and the extent of skin blistering revealed the best fit with a non-linear, V-shaped curve with a median break point at 52% EGFR activity (P = 0.0005). Moreover, lapatinib (a dual EGFR/ErbB2 inhibitor) but not erlotinib significantly reduced blistering in the oral cavity, suggesting that signalling mechanisms differ between PV predilection sites. Our results demonstrate that future clinical trials evaluating EGFR/ErbB2 inhibitors in PV patients must select treatment doses that retain a specific level of signal molecule activity. These findings may also be of relevance for cancer patients treated with EGFR inhibitors, for whom skin lesions due to extensive EGFR inhibition represent a major threat.
authors.affiliation: Molecular Dermatology, Institute of Animal Pathology, University of Bern, Bern, Switzerland; DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Beyza S
authors.initials: BS
authors.lastname: Sayar
authors.forename: Simon
authors.initials: S
authors.lastname: Rüegg
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Myriam
authors.initials: M
authors.lastname: Siffert
authors.forename: Maja M
authors.initials: MM
authors.lastname: Suter
authors.forename: Arnaud
authors.initials: A
authors.lastname: Galichet
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D051183:Desmoglein 1 / Q000276:immunology / Q000378:metabolism; D051184:Desmoglein 3 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D000077341:Lapatinib; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017711:Nonlinear Dynamics; D010392:Pemphigus / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051183:Desmoglein 1; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D011799:Quinazolines; D000077341:Lapatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
keywords: EGFR; EGFR inhibitors; c-Myc; erlotinib; lapatinib; p38MAK; pemphigus vulgaris signalling; pilot study