Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition

Linna Zhang, Kathleen Scorsone, Sarah E. Woodfield, Peter Zage

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Purpose: 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.

Original languageEnglish (US)
Pages (from-to)977-987
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume76
Issue number5
DOIs
StatePublished - Nov 1 2015

Keywords

  • Cabozantinib
  • ERK
  • Neuroblastoma
  • RET
  • Retinoic acid
  • XL184

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Fingerprint Dive into the research topics of 'Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition'. Together they form a unique fingerprint.

Cite this