| Autor: |
You, Qing, Chen, Leying, Li, Shuaihu, Liu, Min, Tian, Meng, Cheng, Yuan, Xia, Liangyong, Li, Wenxi, Yao, Yang, Li, Yinan, Zhou, Ying, Ma, Yurui, Lv, Dazhao, Zhao, Longfei, Wang, Hejie, Wu, Zhaoyu, Hu, Jiajun, Ju, Juegang, Jia, Chuanlong, Xu, Nan |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 6/19/2024, Vol. 16 Issue 752, p1-16, 16p |
| Abstrakt: |
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. Editor's summary: Epidermal growth factor receptor inhibitors (EGFRis) are used to treat several common cancers, but EGFRi use is frequently complicated by a skin rash that shows limited response to current treatments. Here, You et al. conducted a transcriptomic analysis of the skin of rats exposed to an EGFRi to uncover early changes preceding rash development, finding early activation of keratinocytes that led to activation of the JAK-STAT pathway and recruitment of inflammatory cells. Topical JAK inhibition ameliorated rash in EGFRi-treated rodents without effects on antitumor efficacy, and a pilot clinical study of topical JAK inhibition in 11 patients with EGFRi-induced rash showed improvement in rash severity, suggesting topical JAK inhibition as a strategy to manage this condition in patients. —Melissa L. Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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