Infigratinib Mediates Vascular Normalization, Impairs Metastasis, and Improves Chemotherapy in Hepatocellular Carcinoma

被引：52

作者：

Hung Huynh ^{[1
]}

Lee, Liek Yeow ^{[1
]}

Goh, Kah Yong ^{[1
]}

Ong, Richard ^{[1
]}

Hao, Huai-Xiang ^{[2
]}

Huang, Alan ^{[2
]}

Wang, Youzhen ^{[3
]}

Porta, Diana Graus ^{[4
]}

Chow, Pierce ^{[5
]}

Chung, Alexander ^{[5
]}

机构：

[1] Natl Canc Ctr, Div Mol & Cellular Res, Mol Endocrinol Lab, 11 Hosp Dr, Singapore 169610, Singapore

[2] Novartis Inst Biomed Res, Cambridge, MA USA

[3] Novartis Inst Biomed Res, Oncol Drug Discovery Pharmacol, Cambridge, MA USA

[4] Novartis Inst Biomed Res Basel, Oncol Translat Res, Basel, Switzerland

[5] Singapore Gen Hosp, Dept Gen Surg, Singapore, Singapore

来源：

HEPATOLOGY | 2019年 / 69卷 / 03期

基金：

英国医学研究理事会;

关键词：

FIBROBLAST-GROWTH-FACTOR; TUMOR VESSEL NORMALIZATION; SELECTIVE INHIBITOR; FACTOR RECEPTORS; GENETIC ALTERATIONS; KINASE INHIBITOR; ANGIOGENESIS; SENSITIVITY; SORAFENIB; CANCER;

D O I：

10.1002/hep.30481

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion, and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug vinorelbine to promote apoptosis, suppress tumor growth, and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 through gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion: Treatments with Infigratinib alone or in combination with vinorelbine may be effective in a subset of patients with HCC with FGFR-driven tumors.

引用

页码：943 / 958

页数：16

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