Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, Japan.
Life Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, Japan.
Int J Mol Sci. 2021 Dec 2;22(23):13071. doi: 10.3390/ijms222313071.
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。索拉非尼已被用作十多年的一线系统治疗药物。然而，对索拉非尼的耐药性限制了患者的反应，在 HCC 治疗中构成了主要障碍。仑伐替尼已被批准作为晚期 HCC 的一线系统治疗药物，是第一个与索拉非尼相比非劣效的药物。因此，在本研究中，我们评估了仑伐替尼在索拉非尼耐药 HCC 细胞中的抑制作用。关于这个主题的研究很少。我们使用两种人 HCC 细胞系 Huh-7 和 Hep-3B 来建立索拉非尼耐药性，并进行了体外和体内研究。仑伐替尼主要通过 ERK 信号诱导 G1 细胞周期停滞来抑制索拉非尼耐药 HCC 细胞的增殖。Hep-3B 索拉非尼耐药细胞对仑伐替尼表现出部分交叉耐药性，可能是由于自噬反应不良所致。总的来说，这些发现表明仑伐替尼克服 HCC 中索拉非尼耐药性的潜在机制涉及 FGFR4-ERK 信号。仑伐替尼可能是一种适合表达 FGFR4 的不可切除 HCC 患者发生索拉非尼耐药后的二线治疗选择。
