<i>FOXO3</i> mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy.

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

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

Author: Shaoxing GUAN ¹ ; Xi CHEN ² ; Youhao CHEN ¹ ; Guohui WAN ¹ ; Qibiao SU ³ ; Heng LIANG ¹ ; Yunpeng YANG ² ; Wenfeng FANG ² ; Yan HUANG ² ; Hongyun ZHAO ² ; Wei ZHUANG ⁴ ; Shu LIU ¹ ; Fei WANG ⁵ ; Wei FENG ¹ ; Xiaoxu ZHANG ¹ ; Min HUANG ¹ ; Xueding WANG ¹ ; Li ZHANG ²
Author Information

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.
Publication Type:Journal Article
Keywords: Autophagy; FOXO3; Gefitinib; Hepatotoxicity; Pharmacogenomics; Pharmacokinetics; Pharmacometabolomic
From: Acta Pharmaceutica Sinica B 2022;12(9):3639-3649
CountryChina
Language:English
Abstract: 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.