FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy
© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Acta pharmaceutica Sinica. B - 12(2022), 9 vom: 11. Sept., Seite 3639-3649 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guan, Shaoxing [VerfasserIn] |
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| Links: |
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| Themen: |
Autophagy |
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| Anmerkungen: |
Date Revised 01.10.2022 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.apsb.2022.02.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM346924383 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a FOXO3 | |
| 650 | 4 | |a Gefitinib | |
| 650 | 4 | |a Hepatotoxicity | |
| 650 | 4 | |a Pharmacogenomics | |
| 650 | 4 | |a Pharmacokinetics | |
| 650 | 4 | |a Pharmacometabolomic | |
| 700 | 1 | |a Chen, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Youhao |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Guohui |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Qibiao |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Heng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yunpeng |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Wenfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Hongyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaoxu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xueding |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Li |e verfasserin |4 aut | |
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