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‐1s (immortalized human...

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Published in:The Journal of pathology 2020-04, Vol.250 (4), p.452-463
Main Authors: Sheen, Yi‐Shuan, Lin, Ming‐Hsien, Tzeng, Wen‐Chia, Chu, Chia‐Yu
Format: Article
Language:English
Subjects:
Cell proliferation
drug eruptions
Endothelial cells
Epidermal growth factor
epidermal growth factor receptor tyrosine kinase inhibitor
Epidermal growth factor receptors
erlotinib
Extracellular signal-regulated kinase
Gene expression
Guanosine triphosphatases
IQGAP1
IQGAP1 protein
Lung cancer
Microvasculature
Nitric oxide
Permeability
Phosphorylation
Protein-tyrosine kinase receptors
Skin diseases
Targeted cancer therapy
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Summary: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.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.5393