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.
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