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

• Published in: The Journal of pathology Vol. 250; no. 4; pp. 452 - 463
• Main Authors: Sheen, Yi‐Shuan, Lin, Ming‐Hsien, Tzeng, Wen‐Chia, Chu, Chia‐Yu
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.04.2020; Wiley Subscription Services, Inc
• 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; Transcription; drug eruptions; endothelial cells; IQGAP1; epidermal growth factor receptor tyrosine kinase inhibitor; erlotinib
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5393

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.