典型文献
FOX03 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy
文献摘要：
Hepatotoxicity is a common side effect for patients treated with gefitinib,but the related pathogenesis is unclear and lacks effective predictor and management strategies.A multi-omics approach integrating pharmacometabolomics,pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution.Here,we found that patients with rs4946935 AA,located in Forkhead Box O3(FOXO3)which is a well-known autophagic regulator,had a higher risk of hepatotox-icity than those with the GA or GG variant(OR=18.020,95％CI=2.473 to 459.1784,P=0.018)in a gefitinib-concentration dependent pattern.Furthermore,functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity,increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury.In contrast,erlotinib-induced liver injury was independent on the variant and expres-sion levels of FOXO3.This study reveals that FOXO3 mutation,leading to autophagic imbalance,plays important role in gefitinib-induced hepatotoxicity,especially for patients with high concentration of ge-fitinib.In conclusion,FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.
文献关键词：
中图分类号：
作者姓名：
Shaoxing Guan;Xi Chen;Youhao Chen;Guohui Wan;Qibiao Su;Heng Liang;Yunpeng Yang;Wenfeng Fang;Yan Huang;Hongyun Zhao;Wei Zhuang;Shu Liu;Fei Wang;Wei Feng;Xiaoxu Zhang;Min Huang;Xueding Wang;Li Zhang
作者机构：
Laboratory of Drug Metabolism and Pharmacokinetics,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510060,China;State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;College of Health Science,Guangdong Pharmaceutical University,Guangzhou 510006,China;Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510080,China;Ersha Department of Pharmacy,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510105,China
文献出处：
引用格式：
[1]Shaoxing Guan;Xi Chen;Youhao Chen;Guohui Wan;Qibiao Su;Heng Liang;Yunpeng Yang;Wenfeng Fang;Yan Huang;Hongyun Zhao;Wei Zhuang;Shu Liu;Fei Wang;Wei Feng;Xiaoxu Zhang;Min Huang;Xueding Wang;Li Zhang-.FOX03 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy)[J].药学学报（英文版）,2022(09):3639-3649
A类：
FOX03,Hepatotoxicity,pharmacometabolomics,pharmacogenomics,rs4946935,hepatotox,fitinib
B类：
mutation,predicting,gefitinib,induced,hepatotoxicity,NSCLC,patients,through,regulation,autophagy,common,side,treated,related,pathogenesis,unclear,lacks,effective,predictor,management,strategies,multi,approach,integrating,pharmacokinetics,was,employed,small,cell,lung,cancer,identify,explore,optional,therapy,substitution,Here,found,that,AA,located,Forkhead,Box,FOXO3,which,well,known,autophagic,regulator,had,higher,risk,than,those,GA,GG,variant,concentration,pattern,Furthermore,functional,experiments,identified,impaired,expression,by,inhibiting,promotor,activity,increasing,threshold,initiation,contributed,liver,injury,In,contrast,erlotinib,independent,levels,This,study,reveals,leading,imbalance,plays,important,role,especially,conclusion,might,be,appropriately,tolerated,treatment,carrying
AB值：
0.467785
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