Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma

Int J Mol Sci. 2020 Dec 10;21(24):9405. doi: 10.3390/ijms21249405.

Abstract

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.

Keywords: angiogenesis inhibitor; growth inhibition; hepatocellular carcinoma; hypoxia; invasion; pan-FGFR inhibitor; vessel normalization.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Apoptosis
  • Bevacizumab / administration & dosage
  • Bevacizumab / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Synergism
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, SCID
  • 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
  • Survivin / genetics
  • Survivin / metabolism
  • Tumor Hypoxia
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Immunological
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Phenylurea Compounds
  • Pyrimidines
  • Survivin
  • Bevacizumab
  • infigratinib
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Extracellular Signal-Regulated MAP Kinases
  • Cdc25c protein, mouse
  • cdc25 Phosphatases