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.
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Li, T., Deng, Y., Shi, Y. et al. Bruton’s tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma. Oncogene 37, 6180–6194 (2018). https://doi.org/10.1038/s41388-018-0397-7
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DOI: https://doi.org/10.1038/s41388-018-0397-7
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