哈卡特
医学
表皮生长因子受体
表皮生长因子受体抑制剂
吉非替尼
皮疹
埃罗替尼
癌症研究
STAT蛋白
药理学
信号转导
一氧化氮
车站3
癌症
细胞培养
内科学
生物
细胞生物学
遗传学
作者
Xinran Xie,Leying Chen,Xin Liu,Zhaoyu Wu,Dazhao Lv,Yurui Ma,Jie Luo,Shiyi Zhang
标识
DOI:10.1016/j.jid.2022.04.026
摘要
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.
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