Treatment of advanced renal cell carcinoma patients with cabozantinib, an oral multityrosine kinase inhibitor of MET, AXL and VEGF receptors

Future Oncol. 2019 Jul;15(20):2337-2348. doi: 10.2217/fon-2019-0021. Epub 2019 Jun 11.

Abstract

Von Hippel-Lindau (VHL), a tumor suppressor gene, is frequently inactivated in renal cell carcinoma (RCC). It drives tumorigenesis by activating downstream hypoxia responsive genes and proangiogenic factors like VEGFR, and is responsible for the activity of tyrosine kinase inhibitors in RCC. Resistance to VEGFR therapy eventually occurs, in part due to activation of alternative signaling pathways like AXL and MET. Cabozantinib is a potent inhibitor of VEGF, AXL and MET receptors providing rationale for its use in RCC. Cabozantinib has been approved for use in the first- and second-line setting in patients with advanced RCC. This manuscript reviews the preclinical data, pharmacology, clinical efficacy and safety of the use of cabozantinib in RCC.

Keywords: AXL; CABOSUN; MET; METEOR; VEGFR; cabozantinib; clinical trial; renal cancer.

Publication types

  • Review

MeSH terms

  • Administration, Oral
  • Anilides / pharmacology
  • Anilides / therapeutic use*
  • Axl Receptor Tyrosine Kinase
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology
  • Clinical Trials as Topic
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / pathology
  • Mutation
  • Neoplasm Staging
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Treatment Outcome
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

  • Anilides
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyridines
  • cabozantinib
  • Von Hippel-Lindau Tumor Suppressor Protein
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • VHL protein, human
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human