EGFR inhibitors erlotinib and lapatinib ameliorate epidermal blistering in pemphigus vulgaris in a non-linear, V-shaped relationship.

Sayar, Beyza S.; Rüegg, Simon; Schmidt, Enno; Sibilia, Maria; Siffert, Myriam; Suter, Maja M.; Galichet, Arnaud; Müller, Eliane Jasmine (2014). EGFR inhibitors erlotinib and lapatinib ameliorate epidermal blistering in pemphigus vulgaris in a non-linear, V-shaped relationship. Experimental dermatology, 23(1), pp. 33-38. Blackwell 10.1111/exd.12290

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > DermFocus
05 Veterinary Medicine > Research Foci > Veterinary Public Health / Herd Health Management
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Public Health Institute
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Sayar, Beyza; Rüegg, Simon; Siffert, Myriam; Suter, Maja; Galichet, Arnaud and Müller, Eliane Jasmine

Subjects:

600 Technology > 630 Agriculture

ISSN:

0906-6705

Publisher:

Blackwell

Language:

English

Submitter:

Susanne Agnes Lerch

Date Deposited:

24 Mar 2015 14:45

Last Modified:

22 Oct 2015 08:51

Publisher DOI:

10.1111/exd.12290

PubMed ID:

24279293

Uncontrolled Keywords:

EGFR, EGFR inhibitors, c-Myc, erlotinib, lapatinib, p38MAK, pemphigus vulgaris signalling, pilot study

BORIS DOI:

10.7892/boris.65585

URI:

https://boris.unibe.ch/id/eprint/65585

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