Purpuric drug eruptions induced by EGFR tyrosine kinase inhibitors are associated with IQGAP1-mediated increase in vascular permeability
Journal
Journal of Pathology
Journal Volume
250
Journal Issue
4
Pages
452-463
Date Issued
2020
Author(s)
Abstract
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-1s (immortalized human dermal microvascular endothelial cells) and HMVECs (human dermal microvascular endothelial cells), and also inhibited the phosphorylation of EGFR and ERK. We examined the mRNA expression profile of erlotinib-treated HMEC-1s and identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most consistently up-regulated transcript and protein. IQGAP1 was also overexpressed and co-localized 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. ? 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ? 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
SDGs
Other Subjects
actinin; afatinib; alpha actinin 3; alpha catenin; beta catenin; epidermal growth factor receptor; erlotinib; gefitinib; IQ motif containing guanosine triphosphatase activating protein 1; lmo7 protein; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 3; nectin 1; protein kinase B; protein tyrosine kinase inhibitor; stress activated protein kinase; unclassified drug; vascular endothelial cadherin; guanosine triphosphatase activating protein; IQ motif containing guanosine triphosphatase activating protein 1; protein kinase inhibitor; quinazoline derivative; adherens junction; Article; blood vessel permeability; cell contact; confocal microscopy; controlled study; dermal microvascular endothelial cell; drug eruption; electric resistance; gene expression; human; human cell; immunofluorescence; in vitro study; keratinocyte; priority journal; protein expression; protein phosphorylation; purpuric rash; real time polymerase chain reaction; RNA interference; upregulation; Western blotting; capillary permeability; drug effect; drug eruption; drug resistance; endothelium cell; genetics; lung tumor; metabolism; mutation; non small cell lung cancer; pathology; proto oncogene; tumor cell line; Capillary Permeability; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Eruptions; Drug Resistance, Neoplasm; Endothelial Cells; Genes, erbB-1; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Quinazolines; ras GTPase-Activating Proteins
Publisher
John Wiley and Sons Ltd
Type
journal article