Prophylactic Effect of Nitric Oxide Donors on Rat Models of EGFR Inhibitor‒Induced Cutaneous Toxicities.

Abstract

EGF receptor (EGFR) inhibitors have been established as first-line standard-of-care therapies for nonsmall cell lung cancer but are frequently accompanied by adverse dermatological effects, in particular, acneiform rash. There is no effective clinical intervention, partially because of its poorly understood etiology. In this study, we show that inhibition of EGFR initiated keratinocyte HaCaT cell cycle arrest and apoptosis, which fueled a robust secondary inflammatory response. Rats gavaged with EGFR inhibitor showed a phenotype similar to that of clinical patients, which was in line with the interrupted functions observed in HaCaT keratinocytes. We found that a nitric oxide donor, nitroglycerin, was a feasible treatment alternative for EGFR inhibitor‒induced rash. Restoration of epidermal extracellular signal‒regulated kinase and a reduction in signal transducer and activator of transcription 3 signaling through nitroglycerin treatment rescued the cellular functions that had been damaged in vitro and further ameliorated the rash in rat models. In addition, the efficacy of nitroglycerin was superior to that of existing clinical interventions. These data highlighted the importance of epidermal EGFR signaling and led to the identification of a small-molecule nitric oxide donor as a mediator that can maintain EGFR pathway functions during anti-EGFR therapies, providing a therapeutic anchor point for adverse EGFRI-induced skin effects.

• Authors: Xinran Xie, Leying Chen, Xin Liu, Zhaoyu Wu, Dazhao Lv, Yurui Ma, Jie Luo, Shiyi Zhang
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 142 Issue 11 Pg. 3052-3061.e8 (11 2022) ISSN: 1523-1747 [Electronic] United States
• PMID: 35618045 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Nitric Oxide Donors
• STAT3 Transcription Factor
• Nitroglycerin
• ErbB Receptors
• Protein Kinase Inhibitors
• Extracellular Signal-Regulated MAP Kinases

Topics

• Rats
• Animals
• Nitric Oxide Donors (pharmacology, therapeutic use)
• STAT3 Transcription Factor (metabolism)
• Carcinoma, Non-Small-Cell Lung
• Nitroglycerin (pharmacology)
• Lung Neoplasms
• ErbB Receptors (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Skin Diseases
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Exanthema