Topical JAK inhibition ameliorates EGFR inhibitor–induced rash in rodents and humans

表皮生长因子受体抑制剂 皮疹 药理学 阿法替尼 医学 吉非替尼 趋化因子 免疫系统 表皮生长因子受体 免疫学 癌症研究 癌症 内科学
作者
Qing You,Leying Chen,Shuaihu Li,Min Liu,Meng Tian,Yuan Cheng,Liang-Yong Xia,Wenxi Li,Yang Yao,Yinan Li,Ying Zhou,Yurui Ma,Dazhao Lv,Longfei Zhao,Hejie Wang,Zhaoyu Wu,Jiajun Hu,Juegang Ju,Chuanlong Jia,Nan Xu,Jie Luo,Shiyi Zhang
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:16 (752)
标识
DOI:10.1126/scitranslmed.abq7074
摘要

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)–signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
1秒前
奇奇吃面完成签到,获得积分10
1秒前
所所应助科研通管家采纳,获得10
1秒前
Lucas应助科研通管家采纳,获得30
2秒前
田様应助科研通管家采纳,获得30
2秒前
慕青应助科研通管家采纳,获得10
2秒前
Ava应助科研通管家采纳,获得10
2秒前
2秒前
小马甲应助科研通管家采纳,获得10
2秒前
2秒前
不安青牛应助科研通管家采纳,获得10
2秒前
xiaoming应助科研通管家采纳,获得10
2秒前
科研通AI2S应助科研通管家采纳,获得10
2秒前
星辰大海应助科研通管家采纳,获得10
2秒前
酷波er应助科研通管家采纳,获得20
3秒前
科研通AI2S应助科研通管家采纳,获得10
3秒前
不安青牛应助科研通管家采纳,获得10
3秒前
汉堡包应助科研通管家采纳,获得10
3秒前
不安青牛应助科研通管家采纳,获得10
3秒前
香蕉觅云应助科研通管家采纳,获得10
3秒前
科研通AI2S应助科研通管家采纳,获得10
3秒前
CodeCraft应助jing采纳,获得10
3秒前
5秒前
caleb发布了新的文献求助10
6秒前
imbecile完成签到 ,获得积分10
6秒前
毕业顺利发布了新的文献求助10
7秒前
吱吱吱发布了新的文献求助10
7秒前
秒秒发布了新的文献求助10
7秒前
昨夜星辰完成签到,获得积分10
7秒前
8秒前
犹豫的笑旋完成签到,获得积分10
8秒前
白凉鞋完成签到,获得积分10
9秒前
比耶发布了新的文献求助10
9秒前
10秒前
与共完成签到 ,获得积分10
11秒前
anydwason完成签到,获得积分10
13秒前
酷波er应助futurichest采纳,获得10
13秒前
LILAN应助CNS快求我采纳,获得40
13秒前
13秒前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
Rechtsphilosophie 1000
Bayesian Models of Cognition:Reverse Engineering the Mind 888
Le dégorgement réflexe des Acridiens 800
Defense against predation 800
Very-high-order BVD Schemes Using β-variable THINC Method 568
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3135577
求助须知:如何正确求助?哪些是违规求助? 2786454
关于积分的说明 7777484
捐赠科研通 2442441
什么是DOI,文献DOI怎么找? 1298558
科研通“疑难数据库(出版商)”最低求助积分说明 625193
版权声明 600847