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

Journal article
Authors Joachim T. Siaw
Haiying Wang
Kathrin Pfeifer
V. M. Rivera
Jikui Guan
Ruth H. Palmer
Bengt Hallberg
Published in Oncotarget
Volume 7
Issue 20
Pages 29011-29022
ISSN 1949-2553
Publication year 2016
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 29011-29022
Language en
Links dx.doi.org/10.18632/oncotarget.8508
Keywords anaplastic lymphoma kinase, neuroblastoma, brigatinib, AP26113, resistant mutations, lung-cancer, activating mutations, single-arm, open-label, crizotinib, tumors, gene, rearrangements, chemotherapy, expression
Subject categories Clinical Medicine

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 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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