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

Oncogene. 2018 Nov;37(47):6180-6194. doi: 10.1038/s41388-018-0397-7. Epub 2018 Jul 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / metabolism*
  • Anaplastic Lymphoma Kinase / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Crizotinib / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neuroblastoma / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human