GPCR-mediated EGFR transactivation ameliorates skin toxicities induced by afatinib  

作　　者：Le-ying Chen Qing You Da-zhao Lv Shuai-hu Li Shi-yi Zhang 

机构地区：[1]School of Biomedical Engineering,Shanghai Jiao Tong University,Shanghai 200240,China

出　　处：《Acta Pharmacologica Sinica》2022年第6期1534-1543,共10页中国药理学报（英文版）

基　　金：This work was,in part,supported by the Youth Thousand Talents Program of China,start-up grants from the Shanghai Jiao Tong University(WF220408211);This work was also supported by the grants from the State Key Laboratory of Onco-genes and Related Genes(90-17-02);from the Interdisciplinary Program of Shanghai Jiao Tong University(YG2017MS18).

摘　　要：Many G-protein-coupled receptor(GPCR)agonists have been studied for transactivating epidermal growth factor receptor(EGFR)signaling through extracellular or intracellular pathways.Accumulated evidence has confirmed that GPCR transactivation participates in various diseases.However,the clinical application of GPCR transactivation has not been explored,and more translational studies are needed to develop therapies to target GPCR-mediated EGFR transactivation.In cancer patients treated with EGFR inhibitors(EGFRi),especially afatinib,a unique acneiform rash is frequently developed.In this study,we first established the connection between GPCR transactivation and EGFRi-induced skin disease.We examined the ability of three different GPCR agonists to reverse signaling inhibition and ameliorate rash induced by EGFRi.The activation of different agonists follows unique time and kinase patterns.Rats treated with EGFRi show a similar skin phenotype,with rash occurring in the clinic;correspondingly,treatment with GPCR agonists reduced keratinocyte apoptosis,growth retardation and infiltration of inflammatory cytokines by transactivation.This phenomenon demonstrates that EGFR inhibition in keratinocytes regulates key factors associated with rash.Our findings indicate that maintaining EGFR signaling by GPCR agonists might provide a possible therapy for EGFR inhibitor-induced skin toxicities.Our study provides the first example of the translational application of GPCR transactivation in treating diseases.

关 键 词：GPCR agonist EGFR transactivation EGFR inhibitor RASH 

分 类 号：R285.5[医药卫生—中药学]