Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo
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Zhenghu Chen1,2, Yanling Zhao2, Yang Yu2, Jonathan C. Pang2,3, Sarah E. Woodfield4, Ling Tao2, Shan Guan2, Huiyuan Zhang2, Shayahati Bieerkehazhi5,6, Yan Shi4, Roma Patel4, Sanjeev A.Vasudevan4, Joanna S. Yi2, Jodi A. Muscal2, Guo-Tong Xu1 and Jianhua Yang2
1Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
2Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA
3Department of Biosciences, Weiss School of Natural Sciences, Rice University, Houston, Texas 77005, USA
4Division of Pediatric Surgery, Texas Children’s Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA
5Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
6Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
Joanna S. Yi, email: [email protected]
Jodi A. Muscal, email: [email protected]
Guo-Tong Xu, email: [email protected]
Jianhua Yang, email: [email protected]
Keywords: neuroblastoma, RET, regorafenib, chemotherapy, tyrosine kinase inhibitor
Received: July 26, 2017 Accepted: September 29, 2017 Published: October 24, 2017
Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both in vitro and in vivo. We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a TH-MYCN transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of TH-MYCN transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.
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