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

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Li T,Deng Y,Shi Y,Tian R,Chen Y,Zou L,Kazi JU,Rönnstrand L,Feng B,Chan SO,Chan WY,Sun J,Zhao H

doi

10.1038/s41388-018-0397-7

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

6180-6194

issue

47

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-018-0397-7

journal_volume

37

pub_type

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