Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor‐4 inhibition in hepatocellular carcinoma

Abstract

The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron‐dependent accumulation of lethal lipid reactive oxygen species (ROS). Nuclear factor erythroid‐derived 2‐like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib‐induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib‐induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor‐4 (FGFR4) or Nrf2 and overexpressing‐Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system Xc− (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing‐FGFR4 suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2‐silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2‐overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low‐FGFR4 expression than in those with high‐FGFR4 expression. Patients with FGFR4‐positive HCC displayed significantly longer progression‐free survival than those with FGFR4‐negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib.

Lenvatinib plus transarterial chemoembolization with or without immune checkpoint inhibitors for unresectable hepatocellular carcinoma: A review

“…After PD-1 inhibitors therapy, the expression of VEGF and FGF in patients with PD was significantly higher than that of SD patients ( 30 ). Lenvatinib inhibited these angiogenic growth factors and was associated with T-cell activation, enhanced the antitumor immunity, and increased the efficacy of PD-1 inhibitors ( 54 , 55 , 74 ). Additionally, the JAK/STAT3 signaling pathway was activated by FGFR2 signals accompanied with increasing PD-L1 expression according to Li et al.…”

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma

“…Inhibition of SLC7A11 by sulfasalazine increases ROS levels and suppresses HCC tumor growth [ 43 ]. Recently, Iseda et al reported that lenvatinib, which is another multiple tyrosine kinase inhibitor (TKI) and first-line treatment for HCC, downregulated the expression of SLC7A11 and induced ferroptosis in HCC cells [ 44 ]. The findings described above indicate that HCC cells may be susceptible to ferroptotic cell death triggered by the suppression of SLC7A11, the expression of which was correlated with poorer survival of HCC patients ( Supplementary Figure S3B ).…”

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

“…This is an interesting observation considering that peroxidation of membrane lipids may play a significant role in the mechanism of anticancer action of both drugs. According to the recent studies sorafenib and lenvatinib are also potent inducers of ferroptosis [ 15 , 22 ]—an iron-dependent form of programmed cell death. In case of HCC, ferroptosis is postulated to be one of the main mechanisms responsible for anticancer action of these drugs [ 15 , 22 , 23 ].…”