Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma

• Published in: International journal of molecular sciences 2020-12, Vol.21 (24), p.9405
• Main Authors: Le, Thi Bich Uyen, Vu, Thanh Chung, Ho, Rebecca Zhi Wen, Prawira, Aldo, Wang, Lingzhi, Goh, Boon Cher, Huynh, Hung
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Angiogenesis; Angiogenesis inhibitors; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Agents, Immunological - therapeutic use; Antitumor activity; Apoptosis; Bevacizumab; Bevacizumab - administration & dosage; Bevacizumab - therapeutic use; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cdc2 protein; cdc25 Phosphatases - genetics; cdc25 Phosphatases - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Enzyme inhibitors; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibroblast growth factor receptor 2; Fibroblast growth factor receptors; Fibroblasts; Growth factors; Hepatocellular carcinoma; Hypoxia; Immunotherapy; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medical prognosis; Metastases; Metastasis; Mice; Mice, SCID; Monoclonal antibodies; Neoplasm Metastasis; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - therapeutic use; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal transduction; Survivin; Survivin - genetics; Survivin - metabolism; Targeted cancer therapy; Tumor Hypoxia; Tumors; Vascular endothelial growth factor; Vascular endothelial growth factor receptors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21249405

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.