Novel Src/Abl tyrosine kinase inhibitor bosutinib suppresses neuroblastoma growth via inhibiting Src/Abl signaling

// Shayahati Bieerkehazhi 1, 2, * , Zhenghu Chen 3, 4, * , Yanling Zhao 4 , Yang Yu 4 , Huiyuan Zhang 4 , Sanjeev A. Vasudevan 5 , Sarah E. Woodfield 5 , Ling Tao 4 , Joanna S. Yi 4 , Jodi A. Muscal 4 , Jonathan C. Pang 4, 6 , Shan Guan 4 , Hong Zhang 2 , Jed G. Nuchtern 5 , Hui Li 7 , Huiwu Li 8 , Jianhua Yang 4 1 Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China 2 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 3 Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China 4 Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA 5 Division 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 6 Department of Biosciences, Weiss School of Natural Sciences, Rice University, Houston, Texas 77005, USA 7 Central Laboratory of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China 8 Cancer Prevention and Research Institute, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China * These authors have contributed equally to this work and should be considered co-first authors Correspondence to: Huiwu Li, email: huiwuli1234@163.com Jianhua Yang, email: jianhuay@bcm.edu Keywords: neuroblastoma, bosutinib, SKI-606, Bosulif, chemotherapy Received: October 29, 2016      Accepted: November 12, 2016      Published: November 26, 2016 ABSTRACT Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro . In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.