Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma.
Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma.
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贝伐单抗增强了Infigratinib在肝细胞癌中的抗肿瘤疗效。
DOI：
10.3390/ijms21249405
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发表时间：
2020-12-10
影响因子：
5.6
通讯作者：
Huynh H
中科院分区：
文献类型：
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作者：
Le TBU;Vu TC;Ho RZW;Prawira A;Wang L;Goh BC;Huynh H
成纤维细胞生长因子(成纤维细胞生长因子)信号通路是肝细胞癌的关键信号通路之一。已有研究表明，成纤维细胞生长因子可促进血管内皮细胞生长因子(VEGF)介导的肝细胞癌的发生和血管生成，并可能导致对血管内皮生长因子/血管内皮生长因子受体(VEGFR)靶向药物的耐药性。因此，针对成纤维细胞生长因子/成纤维细胞生长因子受体(FGFR)信号转导的新型药物可能会增强和/或克服肝癌对血管内皮生长因子靶向药物的从头或获得性耐药性。用Infigratinib(一种PAN-FGFR激酶抑制剂)和/或Bevacizumab(一种血管生成抑制剂)治疗高FGFR和低FGFR肿瘤小鼠。两种药物的抗肿瘤活性是单独或联合评估的。肿瘤血管、瘤内缺氧和FGFR信号通路的下游靶点也被研究。当Infigratinib与Bevacizumab联合使用时，对肿瘤的生长、侵袭和肺转移具有协同抑制作用，并显著提高了FGFR依赖的肝癌小鼠的总存活率。Infigratinib/Bevizumab促进细胞凋亡，抑制细胞增殖，同时上调p27，下调FGFR2-4、p-FRS-2、p-ERK1/2、p-p70S6K/4EBP1、CDC25C、Survivin、p-CDc2和p-Rb的表达。联合应用Infigratinib/Bevizumab可为部分伴有FGFR依赖肿瘤的肝癌患者提供治疗益处。高水平的FGFR-2/3可作为Infigratinib/Bevacizumab患者选择的潜在生物标志物。
The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.
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影响因子：
2.4
作者：
Huynh H;Nguyen TT;Chow KH;Tan PH;Soo KC;Tran E
通讯作者：
Tran E
影响因子：
5.3
作者：
Huynh H;Chow KH;Soo KC;Toh HC;Choo SP;Foo KF;Poon D;Ngo VC;Tran E
通讯作者：
Tran E
DOI：
10.1158/1078-0432.ccr-10-2847
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Allen E;Walters IB;Hanahan D
通讯作者：
Hanahan D
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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