FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy  

作　　者：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 

机构地区：[1]Laboratory of Drug Metabolism and Pharmacokinetics,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510060,China [2]State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou 510060,China [3]College of Health Science,Guangdong Pharmaceutical University,Guangzhou 510006,China [4]Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510080,China [5]Ersha Department of Pharmacy,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510105,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第9期3639-3649,共11页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (Grant Nos. 81973398, 81473283, 81730103, 81573507 and 82020108031);The National Key Research and Development Program (Grant Nos. 2017YFC0909300 and 2016YFC0905000, China);Guangdong Provincial Key Laboratory of Construction Foundation (Grant No. 2017B030314030, China);Science and Technology Program of Guangzhou (201607020031, China);National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province (No. 2017B090903004, China);the 111 project (Grant: B16047, China);China Postdoctoral Science Foundation (Grant Nos. 2019M66324, 2020M683140 and 2020M683139)

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 hepatotoxicity 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 expression 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 gefitinib.In conclusion,FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

关 键 词：GEFITINIB HEPATOTOXICITY Pharmacometabolomic PHARMACOKINETICS PHARMACOGENOMICS FOXO3 AUTOPHAGY 

分 类 号：R969[医药卫生—药理学]