title: Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition.
abstract: OBJECTIVE
  Children with high-risk neuroblastoma have poor survival rates, and novel therapies are needed. We hypothesized that cabozantinib would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of receptor tyrosine kinase signaling pathways.
  
  
  METHODS
  We determined neuroblastoma cell viability after treatment with cabozantinib alone and in combination with 13-cis-retinoic acid, topotecan, and temozolomide using MTT assays. Inhibition of RET and intracellular signaling was measured by Western blot analysis of treated and untreated cells. To investigate the efficacy of cabozantinib against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and mice were treated with oral cabozantinib. Tumors were evaluated for growth by determination of in vivo luminescence and final tumor weights.
  
  
  RESULTS
  All neuroblastoma cell lines were sensitive to cabozantinib, and IC50 values ranged from 1.6 to 16.2 μM. Cabozantinib treatment was synergistic with 13-cis-retinoic acid and chemotherapy agents topotecan and temozolomide. Cabozantinib treatment inhibited RET phosphorylation in all cell lines and ERK phosphorylation in more sensitive neuroblastoma cell lines. In mice with neuroblastoma xenograft tumors, cabozantinib treatment significantly reduced tumor growth.
  
  
  CONCLUSIONS
  Treatment of neuroblastoma tumor cells with cabozantinib inhibits RET and ERK phosphorylation and is effective against neuroblastoma tumor cell lines alone and in combination with 13-cis-retinoic acid, topotecan, and temozolomide. Cabozantinib treatment is also effective in reducing tumor growth in vivo. Cabozantinib therefore represents a novel therapeutic agent for neuroblastoma, and further preclinical and clinical studies are warranted.
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Linna
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scorsone
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Woodfield
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA. zage@bcm.tmc.edu.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Zage
mesh_terms: D000284:Administration, Oral; D000310:Adrenal Gland Neoplasms / Q000188:drug therapy; D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D016867:Immunocompromised Host; D020128:Inhibitory Concentration 50; D015474:Isotretinoin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000077204:Temozolomide; D019772:Topotecan / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D003606:Dacarbazine; D019772:Topotecan; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D015474:Isotretinoin; D000077204:Temozolomide
keywords: Cabozantinib; ERK; Neuroblastoma; RET; Retinoic acid; XL184