Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis

Hao Yan, Wentong Wu, Yuhuai Hu, Jinjin Li, Jiangxin Xu, Xueqin Chen, Zhifei Xu, Xiaochun Yang, Bo Yang, Qiaojun He and Peihua Luo ()
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Hao Yan: Zhejiang University
Wentong Wu: Zhejiang University
Yuhuai Hu: Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University
Jinjin Li: Zhejiang University
Jiangxin Xu: Zhejiang University
Xueqin Chen: Zhejiang University School of Medicine, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province
Zhifei Xu: Zhejiang University
Xiaochun Yang: Zhejiang University
Bo Yang: Zhejiang University
Qiaojun He: Zhejiang University
Peihua Luo: Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.

Date: 2023
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DOI: 10.1038/s41467-023-38430-8

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