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The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN

Journal article
Authors Jikui Guan
E. R. Tucker
Haiying Wang
Damini Chand
L. S. Danielson
Kristina Ruuth
Abeer El Wakil
Barbara Witek
Y. Jamin
Ganesh Umapathy
S. P. Robinson
T. W. Johnson
T. Smeal
Tommy Martinsson
L. Chesler
Ruth H. Palmer
Bengt Hallberg
Published in DMM Disease Models and Mechanisms
Volume 9
Issue 9
Pages 941-952
ISSN 1754-8403
Publication year 2016
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 941-952
Language en
Links dx.doi.org/10.1242/dmm.024448
Keywords ALK, Lorlatinib, Mouse models, MYCN, Neuroblastoma, PF-06463922
Subject categories Hematology, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Abstract

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predictedto exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse modelof high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients. © 2016. Published by The Company of Biologists Ltd.

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