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

Joachim T Siaw,Ruth H Palmer,Bengt Hallberg,Jikui Guan,Haiying Wan,Victor M Rivera,Kathrin Pfeifer

doi:10.18632/oncotarget.8508

Joachim T Siaw, Ruth H Palmer + Show 5 more

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https://doi.org/10.18632/oncotarget.8508

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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.

Highlights

The development of pharmacologic strategies targeting anaplastic lymphoma kinase (ALK) reflects the increasing involvement of Anaplastic lymphoma kinase (ALK) in a subset of human malignancies where ALK is well accepted as an initiator and progression marker, representing a tractable oncogene for targeted therapy
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
There has been a significant increase in targeted therapies available for the management of ALK-positive cancers including nonsmall cell lung cancer (NSCLC), inflammatory myofibroblastic tumors (IMT), and anaplastic large cell lymphoma (ALCL)

Summary

Introduction

The development of pharmacologic strategies targeting anaplastic lymphoma kinase (ALK) reflects the increasing involvement of ALK in a subset of human malignancies where ALK is well accepted as an initiator and progression marker, representing a tractable oncogene for targeted therapy. The original discovery of ALK was in 1994, when Morris and colleagues first characterized the ALK gene as a fusion partner of nucleophosmin (NPM), in the NPM-ALK translocation found in a subset of anaplastic large cell lymphoma (ALCL) [1]. An additional ALK inhibitor, alectinib (CH5424802) has been approved in Japan for use in ALK-positive NSCLC [5]. While the above mentioned drugs are all ATP-competitive inhibitors of ALK, they differ in their binding properties and display differential activity in blocking the activity of the various ALK resistant mutant forms [3, 6, 7]. A complex picture of ALK inhibition is emerging, with an increasing number of reports suggesting distinct patterns of resistance mutations arising following primary treatment with particular ALK inhibitors

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