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 pharmacomet...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.展开更多
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)+4 种基金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)
文摘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.
