Oncotarget

Research Papers:

Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent

Jikui Guan, Georg Wolfstetter, Joachim Siaw, Damini Chand, Fredrik Hugosson, Ruth H. Palmer and Bengt Hallberg _

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Oncotarget. 2017; 8:11566-11578. https://doi.org/10.18632/oncotarget.14141

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Abstract

Jikui Guan1, Georg Wolfstetter1, Joachim Siaw1, Damini Chand1, Fredrik Hugosson1, Ruth H. Palmer1, Bengt Hallberg1

1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden

Correspondence to:

Bengt Hallberg, email: [email protected]

Keywords: brigatinib, ATC, ceritinib, crizotinib, neuroblastom

Received: July 26, 2016     Accepted: November 21, 2016     Published: December 24, 2016

ABSTRACT

Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALK-G1201E mutations were originally identified in anaplastic thyroid cancer (ATC) and characterized as constitutively activating mutations. In this study, we employed in vitro cell culture assays together with biochemical and in vivo Drosophila analyses to characterize their sensitivity to either activation by the FAM150A (AUG-β) and FAM150B (AUG-α) ALK ligands or inhibition by ALK inhibitors. Here we report that neither ALK-L1198F nor ALK-G1201E mutations result in ligand independent gain-of-function (GOF) activity in either in vitro biochemical analysis or the various model systems employed. ALK-L1198F is activated by the FAM150 (AUG) ligands and its ligand-dependant activity is similar to the wild type full length ALK receptor. ALK-G1201E is only very weakly activated by the FAM150 (AUG) ligands, most likely due to impaired protein stability. We conclude that neither ALK-L1198F nor ALK-G1201E displays ligand independent kinase activity, with ALK-L1198F belonging to the class of ligand dependent ALK mutations which are not constitutively active but that responds to ligand activation, while the ALK-G1201E mutation generates an unstable receptor with very low levels of kinase activity.


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