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Bruton’s tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma

Oncogenevolume 37pages61806194 (2018) | Download Citation

Abstract

Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton’s tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse-free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination. Both ALKWT and ALKF1174L can induce BTK phosphorylation and higher capacity of ALKF1174L is observed. Furthermore, the BTK inhibitor ibrutinib can effectively inhibit the growth of neuroblastoma xenograft in nude mice, and the combination of ibrutinib and the ALK inhibitor crizotinib further enhances the inhibition. Our study provides strong rationale for clinical trial of ALK-positive neuroblastoma using ibrutinib or the combination of ibrutinib and ALK inhibitors.

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Acknowledgements

We thank Dr. Marc Vigny for kindly providing the ALKWT and ALKF1174L constructs. This work is supported by the Research Grants Council of Hong Kong (CUHK24100414, CUHK14167017) to HZ, the grants from Guangdong Natural Science of Foundation (2017A030313209) and Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018) and Shenzhen Key Laboratory of Cell Microenvironment (ZDSYS20140509142721429) to YD, the National Natural Science Foundation of China (81660473) and West China Top Class Discipline Project (NXYLXK2017B07) in Basic Medical Sciences of Ningxia Medical University to JS, One-off Funding for KIZ-CUHK Joint Lab/Research Collaboration from CUHK to WYC, the National Natural Science Foundation of China (31471367, 31671519) to YC, and TL is supported by the Graduate Studentships from CUHK. We thank colleagues in our laboratories for the helpful discussion.

Author information

Author notes

  1. These authors contributed equally: Tianfeng Li, Yi Deng.

Affiliations

  1. Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

    • Tianfeng Li
    • , Bo Feng
    • , Sun On Chan
    • , Wai Yee Chan
    •  & Hui Zhao
  2. Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004, China

    • Jianmin Sun
  3. Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, 51805, China

    • Yi Deng
    •  & Yonglong Chen
  4. Department of Clinical Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    • Yu Shi
  5. Department of Chemistry, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, Guangdong, 518055, China

    • Ruijun Tian
  6. Center for Clinical Molecular Medicine, Children’s Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China

    • Lin Zou
  7. Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden

    • Julhash U. Kazi
    • , Lars Rönnstrand
    •  & Jianmin Sun
  8. Kunming Institute of Zoology Chinese Academy of Sciences, The Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Hong Kong SAR, China

    • Wai Yee Chan
    •  & Hui Zhao
  9. Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden

    • Lars Rönnstrand
  10. Division of Oncology, Skåne University Hospital, Lund, Sweden

    • Lars Rönnstrand

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Jianmin Sun or Hui Zhao.

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DOI

https://doi.org/10.1038/s41388-018-0397-7