The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.
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Embargo End Date
ICR Authors
Authors
Guan, J
Tucker, ER
Wan, H
Chand, D
Danielson, LS
Ruuth, K
El Wakil, A
Witek, B
Jamin, Y
Umapathy, G
Robinson, SP
Johnson, TW
Smeal, T
Martinsson, T
Chesler, L
Palmer, RH
Hallberg, B
Tucker, ER
Wan, H
Chand, D
Danielson, LS
Ruuth, K
El Wakil, A
Witek, B
Jamin, Y
Umapathy, G
Robinson, SP
Johnson, TW
Smeal, T
Martinsson, T
Chesler, L
Palmer, RH
Hallberg, B
Document Type
Journal Article
Date
2016-09-01
Date Accepted
2016-07-04
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 predicted to 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 model of high-risk neuroblastoma driven by Th-ALK(F1174L)/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.
Citation
Disease models & mechanisms, 2016, 9 (9), pp. 941 - 952
Source Title
Publisher
COMPANY BIOLOGISTS LTD
ISSN
1754-8403
eISSN
1754-8411
Research Team
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Pre-Clinical MRI