Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models.
Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models.
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DOI：
10.1002/cam4.1517
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发表时间：
2018-06
期刊：
影响因子：
4
通讯作者：
Matsui J
中科院分区：
文献类型：
--
作者：
Matsuki M;Hoshi T;Yamamoto Y;Ikemori-Kawada M;Minoshima Y;Funahashi Y;Matsui J
不可切除的肝细胞癌（uHCC）是世界范围内最致命和最普遍的癌症之一，目前针对uHCC的全身治疗选择有限。Lenvatinib是一种靶向血管内皮生长因子受体（VEGFRs）和成纤维细胞生长因子受体（FGFRs）的多受体酪氨酸激酶抑制剂，最近在一项uHCC的3期研究中，通过统计证实索拉非尼的非效性，显示出对总生存的治疗效果。在这里，我们研究了lenvatinib在临床前HCC模型中抗肿瘤活性的机制。对9个人肝癌细胞系的体外增殖实验表明，lenvatinib选择性地抑制FGF信号激活的肝癌细胞的增殖，包括表达Hep3B2.1‐7的FGF19细胞。Lenvatinib在这些细胞中以浓度依赖的方式抑制FRS2 （FGFR1-4的底物）的磷酸化。Lenvatinib抑制Hep3B2.1‐7和SNU‐398异种移植物的体内肿瘤生长，并降低肿瘤组织中FRS2和Erk1/2的磷酸化。Lenvatinib在PLC/PRF/5异种移植模型和两种HCC患者来源的异种移植模型中也具有抗肿瘤活性，并有效降低肿瘤微血管密度。这些结果表明lenvatinib在不同的HCC模型中具有一致的抗肿瘤活性，并且靶向肿瘤FGF信号通路和抗血管生成活性是其抗HCC肿瘤活性的基础。
Unresectable hepatocellular carcinoma (uHCC) is one of the most lethal and prevalent cancers worldwide, and current systemic therapeutic options for uHCC are limited. Lenvatinib, a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs), recently demonstrated a treatment effect on overall survival by statistical confirmation of noninferiority to sorafenib in a phase 3 study of uHCC. Here, we investigated mechanisms underlying the antitumor activity of lenvatinib in preclinical HCC models. In vitro proliferation assay of nine human HCC cell lines showed that lenvatinib selectively inhibited proliferation of FGF signal‐activated HCC cells including FGF19‐expressing Hep3B2.1‐7. Lenvatinib suppressed phosphorylation of FRS2, a substrate of FGFR1–4, in these cells in a concentration‐dependent manner. Lenvatinib inhibited in vivo tumor growth in Hep3B2.1‐7 and SNU‐398 xenografts and decreased phosphorylation of FRS2 and Erk1/2 within the tumor tissues. Lenvatinib also exerted antitumor activity and potently reduced tumor microvessel density in PLC/PRF/5 xenograft model and two HCC patient‐derived xenograft models. These results suggest that lenvatinib has antitumor activity consistently across diverse HCC models, and that targeting of tumor FGF signaling pathways and anti‐angiogenic activity underlies its antitumor activity against HCC tumors.
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影响因子：
3.8
作者：
Miura S;Mitsuhashi N;Shimizu H;Kimura F;Yoshidome H;Otsuka M;Kato A;Shida T;Okamura D;Miyazaki M
通讯作者：
Miyazaki M
DOI：
10.3390/diseases3040294
发表时间：
2015-10-28
期刊：
Diseases (Basel, Switzerland)
影响因子：
--
作者：
Repana D;Ross P
通讯作者：
Ross P
影响因子：
9.7
作者：
Okamoto, Kiyoshi;Kodama, Kotaro;Tsuruoka, Akihiko
通讯作者：
Tsuruoka, Akihiko
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
8
作者：
Courau, Tristan;Nehar-Belaid, Djamel;Klatzmann, David
通讯作者：
Klatzmann, David