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Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice

Siaw, Joachim T. LU orcid ; Wan, Haiying ; Pfeifer, Kathrin ; Rivera, Victor M. ; Guan, Jikui ; Palmer, Ruth H. and Hallberg, Bengt (2016) In Oncotarget 7(20). p.29011-29022
Abstract

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. ALK mutations are reported in about 5-7% of neuroblastoma cases but the ALK-positive percentage increases significantly in the relapsed patient population. Crizotinib, the first clinically approved ALK inhibitor for the treatment of ALK-positive lung cancer has had less dramatic responses in neuroblastoma. Here we investigate the efficacy of a second-generation ALK inhibitor, brigatinib, in a neuroblastoma setting. Employing neuroblastoma cell lines, mouse xenograft and Drosophila melanogaster model systems expressing different constitutively active ALK variants, we show clear and efficient inhibition of... (More)

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. ALK mutations are reported in about 5-7% of neuroblastoma cases but the ALK-positive percentage increases significantly in the relapsed patient population. Crizotinib, the first clinically approved ALK inhibitor for the treatment of ALK-positive lung cancer has had less dramatic responses in neuroblastoma. Here we investigate the efficacy of a second-generation ALK inhibitor, brigatinib, in a neuroblastoma setting. Employing neuroblastoma cell lines, mouse xenograft and Drosophila melanogaster model systems expressing different constitutively active ALK variants, we show clear and efficient inhibition of ALK activity by brigatinib. Similar abrogation of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. These results suggest that brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma that should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.

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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anaplastic lymphoma kinase, AP26113, Brigatinib, Neuroblastoma, Resistant mutations
in
Oncotarget
volume
7
issue
20
pages
29011 - 29022
publisher
Impact Journals
external identifiers
  • scopus:84969850857
  • pmid:27049722
ISSN
1949-2553
DOI
10.18632/oncotarget.8508
language
English
LU publication?
no
id
5b5e84e6-c65d-4b7b-be5f-f0c3fcdfd477
date added to LUP
2025-03-19 11:47:33
date last changed
2025-07-10 05:30:46
@article{5b5e84e6-c65d-4b7b-be5f-f0c3fcdfd477,
  abstract     = {{<p>Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. ALK mutations are reported in about 5-7% of neuroblastoma cases but the ALK-positive percentage increases significantly in the relapsed patient population. Crizotinib, the first clinically approved ALK inhibitor for the treatment of ALK-positive lung cancer has had less dramatic responses in neuroblastoma. Here we investigate the efficacy of a second-generation ALK inhibitor, brigatinib, in a neuroblastoma setting. Employing neuroblastoma cell lines, mouse xenograft and Drosophila melanogaster model systems expressing different constitutively active ALK variants, we show clear and efficient inhibition of ALK activity by brigatinib. Similar abrogation of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. These results suggest that brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma that should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.</p>}},
  author       = {{Siaw, Joachim T. and Wan, Haiying and Pfeifer, Kathrin and Rivera, Victor M. and Guan, Jikui and Palmer, Ruth H. and Hallberg, Bengt}},
  issn         = {{1949-2553}},
  keywords     = {{Anaplastic lymphoma kinase; AP26113; Brigatinib; Neuroblastoma; Resistant mutations}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{20}},
  pages        = {{29011--29022}},
  publisher    = {{Impact Journals}},
  series       = {{Oncotarget}},
  title        = {{Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice}},
  url          = {{http://dx.doi.org/10.18632/oncotarget.8508}},
  doi          = {{10.18632/oncotarget.8508}},
  volume       = {{7}},
  year         = {{2016}},
}