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

// Joachim T. Siaw 1, * , Haiying Wan 1, * , Kathrin Pfeifer 1 , Victor M. Rivera 2 , Jikui Guan 1 , Ruth H. Palmer 1 , Bengt Hallberg 1 1 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 2 ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, USA * Both authors should be considered as first authors Correspondence to: Bengt Hallberg, email: Bengt.Hallberg@gu.se Keywords: anaplastic lymphoma kinase, neuroblastoma, brigatinib, AP26113, resistant mutations Received: November 16, 2015      Accepted: March 18, 2016      Published: March 31, 2016 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.