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

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

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Abbreviations

VEGFR-2:

Vascular endothelial growth factor receptor-2

ATCC:

American Type Culture Collection

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

FBS:

Fetal bovine serum

DMEM:

Dulbecco’s modified Eagle’s medium

MTT:

3-(4,5-Dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide

GDNF:

Glial-derived neurotrophic factor

MTC:

Medullary thyroid cancer

PBS:

Phosphate-buffered saline

CI:

Combination index

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Authors and Affiliations

  1. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA

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

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  1. Linna Zhang
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  2. Kathleen Scorsone
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  3. Sarah E. Woodfield
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Correspondence to Peter E. Zage.

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Characteristics of Neuroblastoma Tumor Cell Lines (XLS 25 kb)

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Zhang, L., Scorsone, K., Woodfield, S.E. et al. Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition. Cancer Chemother Pharmacol 76, 977–987 (2015). https://doi.org/10.1007/s00280-015-2871-z

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