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Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.
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; Luo, Jie; Zhang, Shiyi.
Afiliación
  • You Q; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Chen L; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Li S; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Liu M; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Tian M; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Cheng Y; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Xia L; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Li W; OnQuality Pharmaceuticals LLC., Shanghai 201112, China.
  • Yao Y; OnQuality Pharmaceuticals LLC., Shanghai 201112, China.
  • Li Y; OnQuality Pharmaceuticals LLC., Shanghai 201112, China.
  • Zhou Y; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Ma Y; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Lv D; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Zhao L; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Wang H; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Wu Z; OnQuality Pharmaceuticals LLC., Shanghai 201112, China.
  • Hu J; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Ju J; OnQuality Pharmaceuticals LLC., Shanghai 201112, China.
  • Jia C; Department of Dermatology, Shanghai East Hospital, Tongji University, 150 Jimo Road, Shanghai 200120, China.
  • Xu N; Department of Dermatology, Shanghai East Hospital, Tongji University, 150 Jimo Road, Shanghai 200120, China.
  • Luo J; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • Zhang S; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Sci Transl Med ; 16(752): eabq7074, 2024 Jun 19.
Article en En | MEDLINE | ID: mdl-38896602
ABSTRACT
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Exantema / Receptores ErbB / Inhibidores de las Cinasas Janus Límite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Exantema / Receptores ErbB / Inhibidores de las Cinasas Janus Límite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos