Purpuric drug eruptions induced by EGFR tyrosine kinase inhibitors are associated with IQGAP1-mediated increase in vascular permeability.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used as a treatment for non-small cell lung cancer. There have been some reports of EGFR-TKIs being associated with vascular adverse events. We found that EGFR-TKIs decreased the proliferation of HMEC-1 (immortalized human dermal microvascular endothelial cells) and HMVEC (human dermal microvascular endothelial cells), and also inhibited the phosphorylation of EGFR and ERK. We examined the mRNA expression profile of erlotinib-treated HMEC-1 s and identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most consistently upregulated transcript and protein. IQGAP1 was also over-expressed and colocalized with endothelial cells in the lesional skin. Notably, increased IQGAP1 expression was associated with decreased transendothelial electrical resistance and increased vascular permeability in vitro. Erlotinib treatment enriched the staining of IQGAP1 and reduced the intensities of α-catenin at the sites of cell-cell contact. In conclusion, erlotinib induces adherens junction dysfunction by modulating the expression of IQGAP1 in dermal endothelial cells. This article is protected by copyright. All rights reserved.