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

Authors：Guan, Shaoxing; Chen, Xi; Chen, Youhao; Wan, Guohui; Su, Qibiao; Liang, Heng; Yang, Yunpeng; Fang, Wenfeng; Huang, Yan; Zhao, Hongyun; Zhuang, Wei; Liu, Shu; Wang, Fei; Feng, Wei; Zhang, Xiaoxu; Huang, Min^*; Wang, Xueding^*; Zhang, Li^*

Source：Acta Pharmaceutica Sinica B, 2022, 12(9): 3639-3649.

DOI：10.1016/j.apsb.2022.02.006

• Gefitinib
• Hepatotoxicity
• Pharmacometabolomic
• Pharmacokinetics
• Pharmacogenomics
• FOXO3
• Autophagy

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 nonsmall 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 Z18.020, 95%CIZ 2.473 to 459.1784, PZ0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_Lambda impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinibinduced 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. (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

• Institution
  中山大学; 广州中医药大学; 广东药学院