Vemurafenib impairs the repair of ultraviolet radiation-induced DNA damage

Melanoma Research
Susanne KimeswengerChristian Jantschitsch

Abstract

Targeted therapy with the BRAF inhibitors vemurafenib and dabrafenib is an effective treatment regimen in patients with advanced melanoma carrying the BRAF V600E mutation. A common side effect is an enhanced rate of nonmelanoma skin cancer (NMSC). BRAF inhibition leads to a paradoxical enhanced MAPK signalling in BRAF wild-type cells, which might in part be responsible for the enhanced NMSC burden. It is known that disturbances of DNA repair result in an increased rate of NMSC. In the present study, it was investigated whether BRAF inhibitors might interfere with the repair of ultraviolet radiation-induced DNA damage in vitro. Epidermal keratinocytes of 11 Caucasian donors were treated with vemurafenib or dabrafenib and, 24 h later, exposed to ultraviolet A. DNA damage and repair capacity were analysed using south-western slot blot detecting cyclobutane pyrimidine dimers. Using PCR and DNA sequencing, RAS mutations and human papilloma virus genes were investigated. RNA expression was determined using a Gene Expression Chip and qRT-PCR. In 36% of keratinocytes, vemurafenib hampers the repair of ultraviolet A-induced DNA damage. No changes in DNA repair were observed with dabrafenib, indicating a possible substance-specific effec...Continue Reading

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Citations

Oct 17, 2019·Photodermatology, Photoimmunology & Photomedicine·Markus V HepptMarkus Reinholz
Jun 20, 2020·Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG·Bernadette EberleinChristian Posch
Oct 29, 2020·Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG·Bernadette EberleinChristian Posch
Jan 22, 2022·Briefings in Bioinformatics·Weiping LinXiaochen Bo

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Methods Mentioned

BETA
PCR
protein assay
chip

Software Mentioned

GSEA analysis
GSEA
R
Clustal Omega

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